2004

Veterinary

Neurobiology
(CVM 6120)

Class Notes

by

Alvin J. Beitz, PhD

and

Thomas F. Fletcher, DVM, PhD

 CONTENTS

1: Neurohistology I: Cellular Features .......................3

2: Neurohistology II: Meninges/Receptors...............11

3: Nervous System Development (Embryology) ......18

4: Spinal Cord Organization .....................................31

5: Spinal Reflexes & Neuronal Integration ..............36

6: Cranial Nerves ........................................................44

7: Vestibular System ...................................................50

8: Posture and Movement ..........................................55

9: Cerebral Hemisphere and Cortex.........................60

10: Nociception I ...........................................................65

11: Nociception II .........................................................71

12: Cerebellum ..............................................................76

13: Diencephalon and Hypothalamus .........................81

14: Olfaction and Limbic System ................................86

15: Auditory System .....................................................90

16: Visual System ..........................................................96

2
Lecture 1

Neurohistology I:
Cells and General Features
Overall Objectives: to understand the histological components of nervous tissue;
to recognize the morphological features of neurons; and
to differentiate myelinated from non-myelinated axons

I. Basic Organization:
A. Central Nervous System (CNS)—brain and spinal cord
B. Peripheral Nervous System (PNS)—all cranial and spinal nerves and their associated
roots and ganglia
Functional PNS Divisions:
A. Somatic Nervous System—a one neuron system that innervates (voluntary)
skeletal muscle or somatosensory receptors of the skin, muscle & joints.

B. Autonomic Nervous System—a two neuron visceral efferent system that

innervates cardiac and smooth muscle and glands. It is involuntary
and has two major subdivisions:
1) Sympathetic (thoracolumbar)
2) Parasympathetic (craniosacral)

II. Histological Components:

A. Supporting (non-neuronal) Cells— Glial cells provide support and protection for
neurons and outnumber neurons 10:1. The CNS has three types and the PNS has one:
1. Astrocytes—star-shaped cells that play an active role in brain function by influencing the
activity of neurons. They are critical for 1) recycling neurotransmitters; 2) secreting
neurotrophic factors (e.g., neural growth factor) that stimulate the growth and mainte-
nance of neurons; 3) dictating the number of synapses formed on neuronal surfaces and
modulating synapses in adult brain; and 4) maintaining the appropriate ionic composition
of extracellular fluid surrounding neurons, by absorbing excess potassium and other
larger molecules.
2. Oligodendrocytes— The oligodendrocyte is the analog of the Schwann cell in the central
nervous system and is responsible for forming myelin sheaths around brain and spinal
cord axons. Myelin is an electrical insulator.
3. Microglia—are the smallest of glial cells. They represent the intrinsic immune effector
cells of the CNS and underlie the inflammation response that occurs following damage to
the central nervous system and the invasion of microorganisms.
4. Lemmocytes (Schwann Cells)— Schwann cells are glia cells of the PNS. They wrap
individually around the shaft of peripheral axons, forming a layer or myelin sheath along
segments of the axon. The Schwann cell membrane, which forms the myelin sheath, is
composed primarily of lipids; the lipid serves as an insulator thereby speeding the trans-
mission rate of action potentials along the axon.
3
 5. Ependyma — in addition to the above glial cells, the CNS has epithelial-like cells that line
the ventricles of the brain and the central canal of the spinal cord.

Note: Glial cells are capable of reproduction, and when control over this capacity is lost
primary brain tumors result. Astrocytomas and glioblastomas are amongst the
most deadly or malignant forms of cancer.

B. Neurons (nerve cells)—neurons are the structural and functional units of the nervous system;
they are specialized to conduct electrical signals.

Note: The plasma membrane of the neuron contains both voltage gated ion channels (in-
volved in generation and conduction of electrical signals) and receptors (which bind neu-
rotransmitters and hormones and use distinct molecular mechanisms for transmembrane
signaling; examples include ligand-gated ion channels and G protein coupled receptors).

1. Morphological Features of neurons (3 component parts; see Fig.1 below):

A. Cell body — the expanded portion of the neuron that contains the nucleus;
— stains basophilically due to the abundance of RER and polyribosomes;
— the clumps of RER & polyribosomes are referred to as Nissl Bodies.

B. Dendrites — one to many extensions of the cell body;

— specialized to receive input from other neurons or from receptors;
— contain Nissl bodies in their proximal parts and thus the initial portions
of dendrites stain basophilically;
— often have small protrusions, called dendritic spines, that expand the
dendritic surface area and serve as sites of synaptic contact.

Multipolar Neuron
input (axon terminal)
(telodendrite) dendrite
cell body (soma) next neuron (dendrite)

telodendritic branches
initial segment (of axon) (with terminal bulbs)
myelin myelin
internode node
axon

axon hillock axon

(of cell body) (conducts excitation)
dendritic zone axontelodendritic
terminal branches
(transmit
zoneneuronal output)
(receives input)

Figure 1: Diagram of a neuron illustrating its component parts

4
 C. Axon — typically one per neuron;
— an extension of the cell body that is specialized for conducting electrical
impulses (action potentials).
— lacks Nissl bodies and does not stain with routine histological stains.
Note: Axons are either myelinated (surrounded by a fatty insulating sheath that speeds
conduction of the electrical impulse) or non-myelinated (lacking a myelin sheath and
thus conduct impulses slowly).

2. Definitions:
A. Ganglion — a collection of neuron cell
Types of Neurons
bodies situated in the PNS dendrite
B. Nucleus — this term is used in a special
sense in neurobiology to describe a collection of telodendria
(synapse in CNS)
neuronal cell bodies in the CNS (accumulation of
gray matter) coiled proximal
C. Nerves — bundles of axons that extend axon

out from the brain as cranial nerves and from the

spinal cord as spinal nerves (surrounded by connec-

axon
tive tissue sheaths) axon hillock
(of cell body) cell body
D. Tract — a bundle of axons (nerve fibers)
within the CNS (connective tissue is absent) cell body

Bipolar Unipolar Multipolar

3. Neuronal Classification: Neuro Neuron Neuron

A. Anatomically, by number of processes:

1) Unipolar (pseudounipolar)
Neuron — has one process that bifurcates; the cell
body of this neuronal type is found in spinal and
axon

cranial ganglia. cell body

2) Bipolar Neuron — has 2 pro- receptor
(free nerve
cesses (relatively rare; retina of eye and certain endings)
cranial ganglia).
3) Multipolar Neuron — many dendritic zone
processes; typically 1 axon and 2 or more dendrites (synapses on
hair cells of
(most common type of neuron). cochlea) telodendria

B. Functionally:
1) Motor (Efferent) — related to innervation of muscle, glands etc.; activation of
these neurons leads to some motor event (i.e., contraction of a muscle).

2) Sensory (Afferent) — related to the transfer of sensory information (i.e., pain,

touch, pressure, etc.); e.g., neurons of spinal (dorsal root) ganglia.

3) Interneurons — neither motor or sensory (e.g., neurons responsible for the various
spinal reflexes).
5
Fig. 3. Peripheral nerve tissue (light microscopy).

Top. Longitudinal illustration of a myelinated

axon (myelin is gray; cytoplasm is black).
Lemmocytes form myelin sheaths around one
axon. Adjacent lemmocytes (myelin sheaths) are
separated by nodes. Cytoplasm filled clefts are
sometimes evident in myelin sheaths.

Right. Myelin sheaths appear as individual black

rings in a transverse section through a nerve
fascicle.

4. Axons:
Axons are neuron processes that project to and synapse with dendrites or cell bodies of other
neurons or with non-neuronal targets (e.g. muscle). Swellings, termed axonal varicosities/boutons,
are found along the axon or at its terminal branches and are typically the sites where synapses occur
(see Neurohistology, Lecture II). Morphologically axons are divided into two types: myelinated and
non-myelinated.

A. MYELINATED AXONS (>1 µm; fast conducting):

Myelinated axons are invested with a membranous, lipid sheath (making them the
largest and fastest conducting nerve fibers). Myelin is a highly organized multilamellar structure
formed by the plasma membrane of oligodendrocytes in the CNS and lemmocytes (Schwann cells)
in the PNS. Myelin is an electrical insulator which allows increased speed of conduction along an
axon. Myelinated axons located in the PNS differ from those in the CNS both in chemical composi-
tion and in the cell type that produces the myelin.
1) Light microscopic appearance:
Under the light microscope, the myelin sheath appears as a tube surrounding the
axon. In H & E or Triple-stained sections, myelin appears like spokes of a wheel around the axon;
this appearance is actually artifactual in that tissue processing (dehydration in alcohols and clearing
in xylene) dissolves lipid components of the myelin leaving nonlipid components. This remaining
protein configuration is called neurokeratin.
2) Nodes of Ranvier:
The nodes are breaks in the continuity of the myelin sheath which occur regularly in
both the peripheral and central nervous systems. They represent the intervals between adjacent
segments of myelin and occur at the junction of two lemmocytes in the PNS or two oligodendrocytes
in the CNS. The nodes appear as constrictions along the nerve fiber.
6
 3) PNS:
In the PNS, a
typical myelinated axon
has the following structure:
axon, surrounded by myelin
sheath, surrounded by
lemmocyte, surrounded by
basal lamina, surrounded
by endoneurium.
The PNS myelin
sheath is richer in phospho-
lipid & has less glycolipid
then CNS myelin. The
myelin is produced by the
membrane of lemmocytes
(Schwann Cells).

Lemmocytes,
derived from neural crest,
are the supporting cells of
the PNS. You will find
them associated with all
peripheral nerve fibers. A Fig. 4: Myelin Paranode—Myelin Node (of Ranvier)—Myelin Paranode
chain of lemmocytes is required to provide myelin for one axon in the PNS.

Myelin Formation—Myelination occurs when the axon attains a diameter > 1 µm. The
lemmocyte wraps around the nerve fiber (axon) several times producing a membranous sheath that
varies in thickness depending on the number of times the lemmocyte wraps around the axon.

Figure 5: Schematic diagram illustrating the different phases of

myelin formation in peripheral nerves.
7
 Myelin Development (PNS)

N neurolemmocyte
N
a

A
B a
nonmyelinated axon mesaxon

a
C
N a
myelin
sheath

E D

Figure 6: Diagrams showing features of myelinated and non-myelinated

nerve fiber development.

4) CNS:
The myelin sheath is produced by oligodendrocytes (one of the CNS glial cells). A
single oligodendrocytes will provide myelin for multiple axons. CNS myelin has more
glycolipid and less phospholipid than PNS myelin. In the CNS, myelinated axons lack a
basal lamina and endoneurium.

8
 Clinical Correlation

Demyelination - Demyelination is the destructive removal of

myelin, an insulating and protective fatty protein that sheaths nerve cell
axons. When axons become demyelinated, they transmit the nerve im-
pulses 10 times slower than normal myelinated ones and in some cases
they stop transmitting action potentials altogether. There are a number of
clinical diseases associated with the breakdown and destruction of the
myelin sheath surrounding brain, spinal cord or peripheral nerve axons.

Degenerative myelopathy, for instance, is a progressive disease of

the spinal cord in older dogs. The breeds most commonly affected include
German Shepherds, Welsh Corgis, Irish Setters and Chesapeake Bay
Retrievers. The disease begins in the thoracic area of the spinal cord and
is associated with degeneration of the myelin sheaths of axons that com-
prise the spinal cord white matter. The affected dog will wobble when
walking, knuckle over or drag their feet, and may cross their feet. As the
disease progresses, the limbs become weak and the dog begins to buckle at
the knees and have difficulty standing. The weakness gets progressively
worse until the dog is unable to walk.

Note:
Unlike the PNS, axons in the CNS do not regenerate following
injury. In part, this is due to the fact that CNS myelin contains several
proteins that inhibit axonal regeneraltion.

B. NON-MYELINATED AXONS (< 1 µm; slow conducting):

1) PNS — Non-myelinated axons are embedded in infoldings of the plasma membrane of a

chain of lemmocytes. Each lemmocyte typically encloses 5-20 axons (see Fig. 5, previous page).
Axoplasm clumps and stains poorly with routine histological stains. A group of axons and associ-
ated lemmocytes are surrounded by basal lamina and endoneurium.

2) CNS — Nonmyelinated axons are not associated with oligodendrocytes but run free
without any type of ensheathment. They are separated from one another by astrocytic processes.

9
 Size Range of Peripheral Nerve Fibers

Efferent Nerve Fibers Fiber Diameter Afferent Nerve Fibers

20 µ
—
Extrafusal muscle fibers —
annulospiral spindle endings Ia
—large motor units —
16 µ
ALPHA —
—
tendon organs
Ib
—
A Extrafusal muscle fibers 12 µ
—small motor units —
— secondary spindle endings
BETA
— encapsulated receptors in II
— joints and skin

GAMMA Intrafusal muscle fibers —

6 µ
—
DELTA — hair follicle receptors
3 µ
—
free ending mechanoreceptors
pricking pain receptors
III
B GVE Preganglionic —
1 µ
non-myelinated slow pain nociceptors
C GVE Postganglionic
0.2 µ thermoreceptors IV
NOTE: Nerve fiber = axon + myelin for myelinated fibers and axon for nonmyelinated fbers.
Conduction velocity (m/sec) = fiber diameter (µm) X 6 (approximately).
Thus, a 20µm fiber conducts at approximately 120m/s = 270 mph.

Two classification schemes for peripheral nerve fibers:

1] Based solely on nerve fiber diameter (I—IV). . .
commonly applied to afferent fibers.

2] Derived from the compound action potential:

α
Compound Action Potential
(hypothetical)
β
γ
δ
A B C
10
Lecture 2

Neurohistology II:
Synapses, Meninges, & Receptors
Overall Objectives: To understand the concept of the synapse; to understand the concept of
axonal transport; to learn to identify the three layers of the meninges; and to understand
how receptors are classified.

I. The Synapse:
The synapse is a specialized point of functional contact between neurons or between a neuron and
a target organ (i.e., muscle) that allows neurons to communicate with one another or with their target
cells.

Synaptic Anatomy . . .
The synpase is a site of apposi-
tion between a presynaptic element of
one neuron and a postsynaptic mem-
brane of a target neuron (or an effector
organ); where, typically, a presynaptic
axon enlargement releases transmitter
molecules that diffuse across a synap-
tic cleft and bind to receptor channels
in the postsynaptic membrane.

Synapses are comprised of three

elements:
a) Presynaptic nerve terminal —
contains synaptic vesicles
which house a chemical
neurotransmitter that is re-
leased after vesicle fusion with
the presynaptic terminal
plasma membrane.

b) Postsynaptic element— a
dendrite, a cell body, or a
target cell receiving the synap-
tic input. Receptor protein
molecules, to which neu-
rotransmitter molecules bind,
are embedded in the postsyn-
aptic plasma membane.

c) Synaptic Cleft— a gap between pre- and post-synaptic elements into which neurotransmitter
molecules are released.

11
Common presynaptic arrangements:
1) axon terminal branches have terminal enlargements (called boutons or bulbs)
2) axon terminal branches feature varicosities (for synapses “in passing”)
3) neuromuscular synapse: axon branches have terminal ramifications that form
motor end plates on skeletal muscle fibers.

Terminal En passant Neuromuscular

bulbs varicosities end plates

Classification of synaptic types:

1] axodendritic — axon terminal branch (presynaptic element) synapses on a dendrite;
2] axosomatic — axon terminal branch synapses on a soma (cell body);
3] axoaxonic — axon terminal branch synapses on another axon terminal branch
(for presynaptic inhibition) or beside the initial segment of an axon;
4] dendrodendritic — dendrite synapsing on another dendrite (very localized effect).

Synaptic ultrastructure:

• The presynaptic enlargement Mitochondrion

(bouton, varicosity, or end Microtubule Presynaptic
plate) contains synaptic Neurofilament terminal bulb
vesicles (20 nm diameter), clus-
tered around an electron dense
active zone (protein-rich Astrocyte
plasma membrane). Vesicles are
anchored in place by actin Synaptic
microfilaments. vesicle

• Pre- and postsynaptic plasma

membranes are separated by a
synaptic cleft (20 nm wide). The
cleft contains glycoprotein Synaptic
linking material and is sur- cleft
rounded by glial cell processes.
Postsynaptic dendrite
• The postsynaptic plasma mem-
brane may appear unremark-
able or thickened (electron dense). Receptor proteins (typically ligand-gated channels) are
embedded in the plasma membrane.

12
Synaptic Physiology . . .
Presynaptic events:
Neurotransmitter molecules are released in proportion to the amount of Ca++ influx, in turn
proportional to the amount of presynaptic membrane depolarization, i.e.,
— in the resting state, the presynaptic membrane is polarized
— when an action potential arrives at the end of the axon, the adjacent presynaptic
membrane is passively depolarized (toward zero transmembrane potential)
— voltage-gated Ca++ channels allow Ca++ influx (driven by [Ca++] gradient).
— elevated [Ca++] triggers vesicle mobilization and docking with the plasma membrane
— a number of vesicles fuse with presynaptic plasma membrane and release
neurotransmitter molecules (about 5,000 per vesicle) by exocytosis.
— transmitter molecules diffuse across the cleft & bind with postsynaptic receptor proteins
— neurotransmitter molecules are eliminated from synaptic clefts via pinocytotic uptake by
presynaptic or glial processes and/or via enzymatic degradation at the postsynaptic
membrane. The molecules are recycled.
— subsequently, presynaptic plasma membrane repolarizes (due to K+ channel conductance).

Postsynaptic events:
Neurotransmitter binding results in a proportional ion flux across the postsynaptic membrane.
The particular excitability effect depends on the nature of the ion flux which depends on the nature
of the ion channels in the particular postsynaptic membrane, i.e.,
— in the resting state, postsynaptic plasma membrane is polarized
(voltage activated K+ channels dominate conductance)
— arriving neurotransmitter molecules bind briefly/repeatedly to ligand-gated receptors, which
opens ion channels directly or by means of second messengers
activation of [Na+ & K+] channels —> leads to depolarization toward zero potential;
activation of Cl- or K+ channels —> hyperpolarization of postsynaptic membrane.
— a postsynaptic potential (PSP) results from the altered membrane conductance
EPSP = Excitatory PSP = depolarization toward zero potential, excites the
postsynaptic cell
IPSP = Inhibitory PSP = hyperpolarization (serves to cancel EPSPs), inhibits the
postsynaptic cell
— following the removal/degradation of Electrotonic Conduction
neurotransmitter molecules, the
postsynaptic membrane is -70
re-polarized (K channel conductance
+

again dominates.) -70

T
Note: PSPs constitute electrotonic conduc- i
tion, a passive voltage spread (in contrast to -70 m
the regenerative conduction of which axons e
0 EPSP
are capable). PSPs decay exponentially, over
distance and with time. The magnitude of a mV
PSP depends on the number of open ion
channels which, in turn, depends on the -70
amount of neurotransmitter released.
Distance
13
 Additional Comments

• synaptic transmission is unidirectional (vesicles are located on only one side).

• glutamate is the major excitatory neurotransmitter in the nervous system; GABA and glycine are the major
inhibitory neurotransmitters.
• synaptic transmission is slower than axonal conduction; each synapse introduces delay into a neural
pathway (at least 0.5 msec/synapse).
• synapses are more susceptible to fatigue, hypoxia, and drug effects than are axons (generally pathways
fail first at synapses).
• different kinds of drugs (tranquilizers, anesthetics, narcotics, anticonvulsants, muscle relaxants, etc.)
work by modifying activity selectively among the different kinds of chemical synapses.
• certain diseases are manifestations of selective synaptic dysfunction; e.g., Parkinson's disease, tetanus,
myasthenia gravis, various intoxications, etc.

II. Connective Tissue Coverings of Axons in the PNS:

1. Endoneurium-- surrounds each myelinated axon, or a group of nonmyelinated axons.

2. Perineurium— surrounds each nerve fascicle (a bundle of axons); consists of a perineural

epithelium and associated collagenous connective tissue. The perineurium participates in forming a
blood-nerve barrier which limits the passage of water-soluble substances and proteins from blood
into the endoneurial compartment. (The integrity of this barrier is altered in certain neuropathies
and following nerve trauma.)

3. Epineurium— surrounds the entire nerve

14
III. Axonal Transport:
1. The net movement of substances along the axon; 2 rates:
A. Fast Axonal Transport—100-500 mm/day
B. Slow Axonal Transport—1-10 mm/day

2. Anterograde Transport—transport of materials down the axon away from the cell body;
important for renewing proteins along the axon and thus maintaining the axon.

3. Retrograde Transport—transport from the axon terminal toward the cell body; important
mechanism by which virus particles (rabies) and neurotoxins (tetanus toxin) gain access to the CNS.
[Note: Tetanus and Botulinum toxins are proteases which cleave neuronal SNARE-proteins.]

IV. Meninges: protective connective tissue sheaths surrounding the brain and spinal cord.
There are three layers of meninges:
1. Dura Mater— the outermost layer consisting of coarse, irregular connective tissue;
composed of collagen and elastic fibers.

2. Arachnoid— middle layer of

the meninges; it consists of a distinct
membrane and numerous fibrous trabecu-
lae on its inner surface. This trabecular
network forms the structural framework for
the subarachnoid space which lies between
the arachnoid proper and the underlying
pia mater.

The subarachnoid space

contains cerebrospinal fluid (CSF). At
certain points the subarachnoid space is
dilated and forms “cisterns”. The cisterna
magna and lumbar cisterns are important
clinically because that is where CSF taps
are performed.
[Note: CSF is a clear colorless
fluid that surrounds and permeates the
entire central nervous system. It functions
to protect, support and nourish the CNS.]

3. Pia Mater—(from the latin term meaning”tender mother”), the innermost layer of the
meninges, it forms a thin protective membrane which adheres to the surface of the brain and spinal
cord. It consists of flattened fibrocytes superficial to elastic and collagen fine fibers that extends into
the numerous depressions and fissures on the surface of the brain and cord. It is very vascular.

15
 Cranial Meninges
Subarachnoid space Arachnoid villus
Dorsal sagittal venous sinus

Dura mater
Arachnoid

Arachnoid
trabecula
Pia mater
Cerebral
cortex
Falx cerebri
White matter

V. Receptors:
1. Receptor = a specialized region located on a peripheral terminal branch of an axon of a
primary afferent neuron, that can serve as a transducer—converting environmental
energy (sensory stimuli) into depolarizing ionic current (nerve signals). The number of
receptors per neuron ranges from several (small receptive field) to several dozen (large
receptive field).
vs.
Sense organ = an organized collection of receptor cells, with which the dendritic zones of afferent neurons
synapse. The excitability of receptor cells is modified by environmental energy, i.e., the receptor cells act
as transducers.
Sense organs are: retina, cochlea,
vestibular apparatus, taste buds, and
olfactory epithelium. Neurons that synapse on
receptor cells are SSA or SVA in type and commonly bipolar rather than unipolar.

2. Classification of receptor populations:

Receptor classification based on Morphology:
1) free nerve endings—terminal branches ramifying among epithelial cells, very
common especially in the skin (mediate pain sensation, itch thermal sensations).
2) tactile discs—consists of a terminal expansions of an afferent axon which are
joined to modified epidermal cells (found in skin and mucous membranes).
3) encapsulated—each receptor is encapsulated by lemmocytes and perineural
epithelium (examples: pacinian corpuscles, tactile corpuscles, muscle spindles).

Receptor classification based on Location:

1) 2) 3)

16
 1) Exteroceptors—associated with skin and subcutaneous tissue (GSA)
2) Proprioceptors—associated with muscles, tendons and joints (GSA)
3) Interoceptors—located in viscera (GVA)

Receptor and sense organ classification based on Modality (energy sensitivity):

1) mechanoreceptors—detect mechanical deformation (touch, pressure, vibration)

2) thermoreceptors—detect changes in temperature (some detect warmth, some detect cold)
3) nociceptors—detect damage to tissue (pain receptors); also detect itch
4) electromagnetic—detect light on the retina of the eye
5) chemoreceptors—detect chemical molecules, including: taste receptors, olfactory
receptors, arterial oxygen receptors in the aortic arch and carotid bodies, blood
osmolarity in the hypothalamus and blood glucose and fatty acid receptors in the
hypothalamus.

Schematic diagram illustrat-

ing various types of periph-
eral receptors:

17
Lecture 3

Development of the Nervous System

and Special Senses
Neurulation
The notochord induces overlaying ectoderm to become neuroectoderm and form a neural
tube. The following stages of neural tube formation are evident:
• neural plate—ectodermal cells overlaying the notochord become tall columnar, producing
a thickened neural plate (in contrast to surrounding ectoderm that produces epidermis of skin).
• neural groove—the neural plate is transformed into a neural groove.
• neural tube—the dorsal margins of the neural groove merge medially, forming a neural
tube composed of columnar neuroepithelial cells surrounding a neural cavity.
In the process of separating from overlaying ectoderm, some neural plate cells become de-
tached from the tube and collect bilateral to it, forming neural crest.

Note: • Neural tube becomes central nervous system (CNS), which consists of
the brain and spinal cord. The cavity of the tube (neural cavity) becomes
the ventricles of the brain and central canal of the spinal cord.
• Neural crest cells become those neurons of peripheral nervous system
(PNS) that have their cell bodies located in ganglia. They also become
neurolemmocytes (Schwann cells) of the PNS. Additionally, neural crest cells
become adrenal medulla cells, melanocytes of skin and a variety of structures in the face.

18
 Central Nervous System
Formation of neurons and glial cells from neuroepithelium:
Neuroepithelium gives rise to neurons, glial cells (astrocytes
and oligodendrocytes), and ependymal cells (additionally, the CNS contains
blood vessels and microglial cells derived from mesoderm).
Neuroepithelial cells have processes which contact the inner and outer
surfaces of the neural tube; they undergo mitotic division in the following manner:
— the nucleus (and perikaryon) moves away from the neural cavity for
interphase (DNA synthesis);
— the nucleus moves toward the neural cavity and the cell becomes
spherical and looses its connection to the outer surface of the neural tube for mito-
sis; this inward-outward nuclear movement is repeated at each cell division.

Some cell divisions are differential, producing neuroblasts

which give rise to neurons or glioblasts (spongioblasts) which give
rise to glial cells (oligodendrogliocytes and astrocytes). Neuroblasts and
glioblasts lose contact with surfaces of the neural tube and migrate
toward the center of the neural tubewall.
Note: Microglial are derived from mesoderm associated with
invading blood vessels.

Layers and plates of the neural tube:

Accumulated neuroblasts and glioblasts form the mantle
layer, a zone of high cell density in the wall of the nerual tube. Cells
that remain lining the neural cavity are designated ependymal cells;
they form an ependymal layer. Surrounding the mantle layer, a cell-
sparse zone where axons of neurons and some glial cells are present
is designated the marginal layer. The mantle layer becomes gray mat-
ter and the marginal layer becomes white matter of the CNS.

The lateral wall of the neural tube is divided

into two regions (plates). A bilateral indentation evi-
dent in the neural cavity (the sulcus limitans) serves
as a landmark to divide each lateral wall into an alar
plate (dorsal) and a basal plate (ventral). Midline re-
gions dorsal and ventral to the neural cavity constitute,
respectively, the roof plate and the floor plate.
The basal plate contains efferent neu-
rons that send axons into the PNS.
The alar plate contains neurons that
receive input from the PNS.
19
 Generally, neurons are incapable of cell division (however, a few neurons do di-
vide, e.g., neurons in olfactory epithelium). The last division of a neuroblast results in
two neurons that are able to migrate but unable to divide.
Note: • A typical neuron has a cell body (perikaryon) and numerous processes emanating from the cell
body. One process, the axon, is generally long and often encased in a myelin sheath formed by
glial cells. Unstained myelin has a white “color”.
• White matter refers to CNS regions that have a high density of myelinated axons. Gray matter
has sparse myelinated axons and generally a high density of neuron cell bodies.

Sculpting Neuronal Circuits

Sculpting – removing excess material to achieve a desired effect

To ensure that all targets get sufficient innervation, initial neural development produces an excessive
number of neurons along with a profuse, random growth of neuronal processes.

Neurons that fail to contact an appropriate target will degenerate and disappear, because they do not
receive sufficient neurotrophic molecules. For the same reason, processes of surviving neurons will
undergo degeneration if they fail to contact an appropriate target (selective pruning). Neurotrophic
molecules are released by target cells to nurture neurons (and by neurons to modify target cells).

Selective degeneration of neurons and neuronal processes is the result of functional competition.
More appropriate targets are associated with more excitation conduction and more neurotransmit-
ter release. Thus developmental remodeling is a consequence of electrochemical activity related to
experiences/behavior. Throughout life, experiences drive nervous system remodeling through
selective growth and pruning of neuronal synapses.

Neuromuscular Innervation
Initially, individual neurons innervate an excessive number of muscle fibers and individual
muscle fibers are innervated by a number motor neurons. Ultimately, motor neurons will innervate only
about 10% of their initial muscle fibers and individual muscle fibers will retain only a single neuromus-
cular synapse.
The survivors (winners) released more neurotransmitter per terminal branch. (Neurons having
fewer branches are able to release more neurotransmitter per terminal branch, giving them a competitive
advantage over neurons with many more processes.)

Neonatal Cortex
In human prefrontal cortex, synaptic density peaks during the first year of age (80K/neuron).
The adult has half that synaptic density (and synaptic spine density). (Note: different studies show differ-
ent timelines for degeneration of neurons and dendrites.)

20
Formation of the Central Nervous System

The cranial end of the

neural tube forms three vesicles
(enlargements) that further di-
vide into the five primary divi-
sions of the brain. Caudal to the
brain the neural tube develops
into spinal cord.

Flexures: During devel-

opment, the brain undergoes three
flexures which generally disappear
(straighten out) in domestic animals.
The midbrain flexure occurs
at the level of the midbrain.
The cervical flexure appears
at the junction between the brain and
spinal cord (it persists slightly in do-
mestic animals).
The pontine flexure is con-
cave dorsally (the other flexures are
concave ventrally).

Adult CNS Structures Derived From Embyonic Brain Divisions

Embryonic Derived Definitive Associated
Brain Division Brain Structures Brain Cavities Cranial Nerves

FOREBRAIN
Telencephalon Cerebrum Lateral ventricles Olfactory (I)

Diencephalon Thalamus; Third Ventricle Optic (II)

hypothalamus; etc.

MIDBRAIN
Mesencephalon Midbrain Mesencephalic aqueduct III & IV

HINDBRAIN
Metencephalon Pons and Cerebellum V
Fourth ventricle
Myelencephalon Medulla Oblongata VI—XII

Note: The portion of brain remaining after the cerebrum and cerebellum are removed is referred to as the brain stem.

21
Spinal cord development
— the neural cavity becomes central canal lined
by ependymal cells;
— growth of alar and basal plates, but not roof
and floor plates, results in symmetrical right and left
halves separated by a ventral median fissure and a dor-
sal median fissure (or septum);
— the mantle layer develops into gray matter,
i.e., dorsal and ventral gray columns separated by intermediate gray matter (in profile, the columns are usually called
horns); cell migration from the basal plate produces a lateral gray column (horn) at thoracic and cranial lumbar levels of
the spinal cord (sympathetic preganglionic neurons);
— the marginal layer becomes white matter (which is subdivided bilaterally into a dorsal funiculus
(bundle), a lateral funiculus, and a ventral funiculus ).

Enlargements of spinal cord segments that innervate limbs (cervical and lumbo-
sacral enlargements) are the result of greater numbers of neurons in those segments,
due to less neuronal degeneration compared to segments that do not innervate limbs.

Hindbrain: Medulla oblongata and pons

— alar plates move laterally and the cavity of the neural tube expands dorsally forming a
fourth ventricle; the roof of the fourth ventricle (roof plate)
is stretched and reduced to a layer of ependymal cells covered
by pia mater; a choroid plexus develops bilaterally in the roof of
the ventricle and secretes cerebrospinal fluid;
— the basal plate (containing efferent neurons
of cranial nerves) is positioned medial to the alar
plate and ventral to the fourth ventricle;
— white and gray matter (marginal & mantle
layers) become intermixed (unlike spinal cord); cer-
ebellar development adds extra structures.

Hindbrain: Cerebellum
NOTE: • Adult cerebellum features surface gray matter, called cerebellar cortex, and three pair of
cerebellar nuclei located deep within the cerebellar white matter. The cerebellum connects to
the brain stem by means of three pair of cerebellar peduncles, each composed of white matter
fibers.
• Cerebellar cortex is composed of three layers: a superficial molecular layer which is rela-
tively acellular; a middle piriform (Purkinje) cell layer consisting of a row of large cell bodies;
and a deep granular (granule cell) layer composed of numerous very small neurons.
• The cerebellum functions to adjust muscle tone and coordinate posture and movement so
they are smooth and fluid vs. jerky and disunited.

— bilateral rhombic lips are the first evidence of cerebellar development; the lips are expan-
sions of the alar plate into the roof plate; the rhombic lips merge medially, forming a midline isthmus (the lips
form the two cerebellar hemispheres and the isthmus forms the vermis of the cerebellum);
22
 — cellular migrations:
• superficial and deep layers of neu-
rons are evident within the mantle layer of the future
cerebellum; the deep cells migrate (pass the superfi-
cial cells) toward the cerebellar surface and become
Purkinje cells of the cerebellar cortex; meanwhile,
neurons of the superficial layer migrate deeply and
become cerebellar nuclei;
• neuroblasts located laterally in the
rhombic lip migrate along the outer surface of the
cerebellum, forming an external germinal layer (which continues to undergo mitosis); subsequently,
neurons migrate deep to the Purkinje cells and form the granule cell layer of the cerebellar cortex;
• some alar plate neurons migrate to the ventral surface of the pons, forming pontine nuclei which send
axons to the cerebellum.

Migration of neuron populations past one another allows connections to be estab-

lished between neurons of the respective populations. Neurons that fail to connect are
destined to degenerate. Connections are made by axons that subsequently elongate as
neurons migrate during growth.

Midbrain
— the neural cavity of the midbrain becomes mesencephalic aqueduct (which is not a ventricle
because it is completely surrounded by brain tissue and thus it lacks a choroid
plexus).
— alar plates form two pairs of dorsal bulges which
become rostral and caudal colliculi (associated with visual and auditory
reflexes, respectively);
— the basal plate gives rise to oculomotor (III) and troch-
lear (IV) nerves which innervate muscles that move the eyes.

Note: The midbrain is the rostral extent of the basal plate (efferent neurons).

Forebrain (derived entirely from alar plate)

Diencephalon:
— the neural cavity expands
dorsoventrally and becomes the
narrow third ventricle, the roof plate
is stretched and choroid plexuses develop
bilaterally in the roof of the third ventricle
and secrete cerebrospinal fluid;

— the floor of the third

ventricle gives rise to the neurohyp-
ophysis (neural lobe of the pituitary
gland);

23
 — the mantle layer of the diencephalon gives rise to thalamus, hypothalamus, etc.; the thal-
amus enlarges to the point where right and left sides meet at the midline and obliterate the center of the third ventricle.
— the optic nerve develops from an outgrowth of the wall of the diencephalon.

Telencephalon (cerebrum):

— bilateral hollow outgrowths become right and left cerebral hemispheres; the cavity of each
outgrowth forms a lateral ventricle that communicates with the third ventricle via an interventricular
foramen (in the wall of each lateral ventricle, a choroid plexus develops that is continuous with a choroid plexus of the
third ventricle via an interventricular foramen);
— at the midline, the rostral end of the telencephalon forms the rostral wall of the third ven-
tricle (the wall is designated lamina terminalis);
— the mantle layer surrounding the lateral ventricle in each hemisphere gives rise to basal
nuclei and cerebral cortex;
— cellular migrations that form cerebral cortex:
• from the mantle layer, cells migrate radially to the surface of the cerebral hemi-
sphere, guided by glial cells that extend from the ventricular surface to the outer surface of the cere-
bral wall (thus each locus of mantle gives rise to a specific area of cerebral cortex);
• migration occurs in waves; the first wave (which becomes the deepest layer of
cortex) migrates to the surface of the cortex; the second wave (which forms the next deepest layer of
cortex) migrates to the cortical surface, passing through first wave neurons which are displaced to a
deeper position; the third wave . . . etc. (the cerebral cortex has six layers.

Cell connections are established within the cerebral cortex as waves of newly
arriving neurons migrate through populations of neurons that arrived earlier.

NOTE: Carnivores are born with a nervous system that does not mature until about six weeks
postnatally (mature behavior is correspondingly delayed). In herbivores, the nervous
system is close to being mature at birth.

24
 Peripheral Nervous System
NOTE: • The peripheral nervous system (PNS) consists of cranial and spinal nerves. Nerve fibers
within peripheral nerves may be classified as afferent (sensory) or efferent (motor) and
as somatic (innervating skin and skeletal muscle) or visceral (innervating vessels and
viscera). The visceral efferent (autonomic) pathway involves two neurons: 1] a pregan-
glionic neuron that originates in the CNS and 2] a postganglionic neuron located entirely
in the PNS. The glial cell of the PNS is the neurolemmocyte (Schwann cell).
• All afferent neurons are unipolar and have their cell bodies in sensory ganglia, either
spinal ganglia on dorsal roots or ganglia associated with cranial nerves. Somatic efferent
and preganglionic visceral efferent neurons have their cell bodies located in the CNS, but
their axons extend into the PNS. Postganglionic visceral efferent neurons have their cell
bodies in autonomic ganglia.

— neurolemmocytes (Schwann cells) arise from neural crest and migrate throughout the
PNS, ensheathing and myelinating axons and forming satellite cells in ganglia;

— afferent neurons orig-

inate from neural crest as bipolar
cells that subsequently become uni-
polar; in the case of cranial nerves,
afferent neurons also originate
from placodes (placode = localized
thickening of ectoderm in the head);

— postganglionic visceral
efferent neurons arise from neural
crest, the cells migrate to form au-
tonomic ganglia at positions within
the head, or beside vertebrae (along
sympathetic trunk), or near the
aorta, or in the gut wall (the latter are
parasympathetic and come from sacral and
hindbrain regions);

— somatic efferent neurons

and preganglionic visceral efferent neurons arise from the basal plate of the neural tube; their cell
bodies remain in the CNS and their axons join peripheral nerves;

Peripheral nerves establish contact early with the nearest somite, somitomere,
placode, or branchial arch and innervate derivatives of these embryonic structures.

Innervation continuity is retained even when the derivatives are considerably displaced
or when other structures have obstructed the pathway. The early establishment of an innervation
connection explains why some nerves travel extended distances and make detours to reach distant
inaccessible targets. The foremost example is the recurrent laryngeal nerve which courses from the brainstem to the
larynx via the thorax, because the heart migrates from the neck to the thorax pulling the nerve with it.

25
 Note: Cranial nerves innervate specific branchial arches and their derivatives:
trigeminal (V) - innervates first branchial arch (muscles of mastication)
facial (VII) - innervates second branchial arch (muscles of facial expression)
glossopharyngeal (IX) - innervates third branchial arch (pharyngeal muscles)
vagus (X) - 4 & 6 branchial arches (muscles of pharynx, larynx, & esophagus)

Formation of Meninges

Meninges surround the CNS and the roots of spinal and cranial nerves.

Three meningeal layers (dura mater, arachnoid, and pia mater) are formed as follows:
— mesenchyme surrounding the neural tube aggregates into two layers;
— the outer layer forms dura mater;
— cavities develop and coalesce within the inner layer, dividing it into arachnoid and pia
mater; the cavity becomes the subarachnoid space which contains cerebrospinal fluid.

26
 Special Senses
Formation of the Eye
Both eyes are derived from a single field of the neural plate. The single field separates into
bilateral fields associated with the diencephalon. The following events produce each eye:
— a lateral diverticulum from the diencephalon forms an optic vesicle attached to the dien-
cephalon by an optic stalk;
— a lens placode develops in the surface ectoderm where it is contacted by the optic vesicle;
the lens placode induces the optic vesicle to invaginate and form an optic cup while the placode
invaginates to form a lens vesicle that invades the concavity of the optic cup;
— an optic fissure is formed by invagination of the ventral surface of the optic cup and optic
stalk, and a hyaloid artery invades the fissure to reach the lens vesicle;

NOTE: The optic cup forms the retina and contributes to formation of the ciliary
body and iris. The outer wall of the cup forms the outer pigmented layer
of the retina, and the inner wall forms neural layers of the retina.
• The optic stalk becomes the optic nerve as it fills with axons traveling
from the retina to the brain.
• The lens vesicle develops into the lens, consisting of layers of lens
fibers enclosed within an elastic capsule.
• The vitreous compartment develops from the concavity of the optic
cup, and the vitreous body is formed from ectomesenchyme that enters the
compartment through the optic fissure.

27
 — ectomesenchyme (from neural crest) surrounding the optic cup condenses to form inner
and outer layers, the future choroid and sclera, respectively;
— the ciliary body is formed by thickening of choroid ectomesenchyme plus two layers of
epithelium derived from the underlying optic cup; the ectomesenchyme forms ciliary muscle and the collage-
nous zonular fibers that connect the ciliary body to the lens;
— the iris is formed by
choroid ectomesenchyme plus the
superficial edge of the optic cup; the
outer layer of the cup forms dilator
and constrictor muscles and the inner
layer forms pigmented epithelium;
the ectomesenchyme of the iris forms
a pupillary membrane that conveys
an anterior blood supply to the de-
veloping lens; when the membrane
degenerates following development
of the lens, a pupil is formed;
— the cornea develops from
two sources: the layer of ectomesen-
chyme that forms sclera is induced
by the lens to become inner epithe-
lium and stroma of the cornea, while
surface ectoderm forms the outer
epithelium of the cornea; the anteri-
or chamber of the eye develops as a
cleft in the ectomesenchyme situated
between the cornea and the lens;
— the eyelids are formed by upper and lower folds of ectoderm, each fold includes a mesen-
chyme core; the folds adhere to one another but they ultimately separate either prenatally (ungulates)
or approximately two weeks postnatally (carnivores); ectoderm lining the inner surfaces of the folds
becomes conjunctiva, and lacrimal glands develop by budding of conjunctival ectoderm;
— skeletal muscles that move the eye (extraocular eye mm.) are derived from rostral somito-
meres (innervated by cranial nerves III, IV, and VI).

Clinical considerations:
• The ungulate retina is mature at birth, but the carnivore retina does not fully mature until about 5
weeks postnatally.
• Retinal detachment occurs between the neural and outer pigmented layers of the retina (inner
and outer walls of the optic cup) which do not fuse but are held apposed by pressure of the vitre-
ous body.
• Coloboma is a defect due to failure of the optic fissure to close.
• Microphthalmia (small eye) results from failure of the vitreous body to exert sufficient pressure
for growth, often because a coloboma allowed vitreous material to escape.
• Persistent pupillary membrane results when the pupillary membrane fails to degenerate and
produce a pupil.

28
Formation of the Ear
The ear has three components: external ear, middle ear, and inner ear. The inner ear contains
sense organs for hearing (cochlea) and detecting head acceleration (vestibular apparatus), the latter
is important in balance. Innervation is from the cochlear and vestibular divisions of the VIII cranial nerve. The
middle ear contains bones (ossicles) that convey vibrations from the tympanic membrane (ear drum)
to the inner ear. The outer ear channels sound waves to the tympanic membrane.

Inner ear:
— an otic placode develops in surface ectoderm adjacent to the hindbrain; the placode in-
vaginates to form a cup which then closes and separates from the ectoderm, forming an otic vesicle
(otocyst); an otic capsule, composed of cartilage, surrounds the otocyst;
— some cells of the placode and vesicle become neuroblasts and form afferent neurons of the vestibulocochlear
nerve (VIII);
— the otic vesicle undergoes differential growth to form the cochlear duct and semicircular
ducts of the membranous labyrinth; some cells of the labyrinth become specialized receptor cells found in macu-
lae and ampullae;
— the cartilagenous otic capsule undergoes similar differential growth to form the osseous
labyrinth within the future petrous part of the temporal bone.

29
Middle ear:
— the dorsal part of the first pharyngeal pouch
forms the lining of the auditory tube and tympanic cavity
(in the horse a dilation of the auditory tube develops into the guttural
pouch);
— the malleus and incus develop as endochondral
bones from ectomesenchyme in the first branchial arch and
the stapes develops similarly from the second arch (in fish,
these three bones have different names; they are larger and function as
jaw bones).

Outer ear:
— the tympanic membrane is formed by appo-
sition of endoderm and ectoderm where the first pharyn-
geal pouch is apposed to the groove between the first and
second branchial arches;
— the external ear canal (meatus) is formed by the groove between the first and second bran-
chial arches; the arches expand laterally to form the wall of the canal and the auricle (pinna) of the
external ear.

Taste buds
Taste buds are groups of specialized (chemoreceptive) epithelial cells localized principally on
papillae of the tongue. Afferent innervation is necessary to induce taste bud formation and maintain
taste buds. Cranial nerves VII (rostral two-thirds of tongue) and IX (caudal third of tongue) innervate the taste buds of
the tongue.

Olfaction
Olfaction (smell) involves olfactory mucosa located caudally in the nasal cavity and the
vomeronasal organ located rostrally on the floor of the nasal cavity. Olfactory neurons are chemore-
ceptive; their axons form olfactory nerves (I).
— an olfactory (nasal) placode appears bilaterally as an ectodermal thickening at the rostral
end of the future upper jaw; the placode invaginates to form a nasal pit that develops into a nasal
cavity as the surrounding tissue grows outward; in the caudal part of the cavity, some epithelial cells
differentiate into olfactory neurons;
— the vomeronasal organ develops as an outgrowth of nasal epithelium that forms a blind
tube; some epithelial cells of the tube differentiate into chemoreceptive neurons.

30
Lecture 4

Spinal Cord Organization

The spinal cord . . .
Afferent
BRAIN tract
• connects with spinal nerves, through afferent neuron

& efferent axons in spinal roots; reflex receptor

interneuron
• communicates with the brain, by means of
cell
ascending and descending pathways that body
form tracts in spinal white matter; and
white matter muscle
• gives rise to spinal reflexes, pre-determined gray matter Efferent neuron
by interneuronal circuits. Spinal Cord Section

Gross anatomy of the spinal cord:

The spinal cord is a cylinder of CNS. The spinal cord exhibits subtle cervical and lumbar
(lumbosacral) enlargements produced by extra neurons in segments that innervate limbs. The
region of spinal cord caudal to the lumbar enlargement is conus medullaris. Caudal to this, a terminal
filament of (nonfunctional) glial tissue extends into the tail.
terminal filament

lumbar enlargement conus medullaris

cervical enlargement

A spinal cord segment = a portion of spinal cord that spinal ganglion

gives rise to a pair (right & left) of spinal nerves. Each spinal
nerve is attached to the spinal cord by means of dorsal and dorsal
root spinal
ventral roots composed of rootlets. Spinal segments, spinal (rootlets) nerve
roots, and spinal nerves are all identified numerically by
region, e.g., 6th cervical (C6) spinal segment. ventral
Sacral and caudal spinal roots (surrounding the conus root
medullaris and terminal filament and streaming caudally to (rootlets)
reach corresponding intervertebral foramina) collectively
constitute the cauda equina.
Both the spinal cord (CNS) and spinal roots (PNS) are
enveloped by meninges within the vertebral canal. Spinal
nerves (which are formed in intervertebral foramina) are
covered by connective tissue (epineurium, perineurium, &
endoneurium) rather than meninges.

Spinal cord histology (transverse section):

Central canal (derived from embryonic neural cavity) is lined by ependymal cells & filled
with cerebrospinal fluid. It communicates with the IV ventricle and ends in a dilated region (terminal ventricle).
Gray matter (derived from embryonic mantle layer) is butterfly-shaped. It has a high
density of neuron cell bodies & gliocytes, a high capillary density, and sparse myelinated fibers.
Gray matter regions include: dorsal horn, ventral horn, and intermediate substance — the latter
features a lateral horn (sympathetic preganglionic neurons) in thoracolumbar spinal segments.
31
 White matter (derived from embryonic marginal layer) is superficial to gray matter. It is
composed of concentrated myelinated fibers, gliocytes, and low capillary density. White matter
regions include: dorsal funiculus; ventral funiculus; lateral funiculus; and white commissure.

dorsal intermediate sulcus dorsal median sulcus and septum

dorsolateral sulcus
dorsal
funciculus
dorsal
horn
lateral
intermediate funiculus
substance
central canal

ventral
horn

ventral white ventral

commissure funiculus

Segment C 6
ventral median fissure

Gray matter organization:

Two schemes have evolved for organizing neuron cell
bodies within gray matter. Either may be used according to
which works best for a particular circumstance.

1] Spinal Laminae—spinal gray matter is divided into

ten laminae (originally based on observations of thick sections in a neona-
tal cat). The advantage is that all neurons are included. The
disadvantage is that laminae are difficult to distinguish.
L7
2] Spinal Nuclei—recognizable clusters of cells are Gray
identified as nuclei [a nucleus is a profile of a cell column]. The Matter
advantage is that distinct nuclei are generally detectable; the Laminae
disadvantage is that the numerous neurons outside of distinct
nuclei are not included.
Selected Spinal Nuclei (Cell Columns)
substantia gelatinosa marginal
nuc.
nuc. intermedio- nuc.
C3 thoracicus lateral nuc. proprius sacral
parasymp.
motor
nuc.
nuc. XI S3
medial T1 0 L6
motor
lateral
nuc.
motor nuc.
32
Types of spinal neurons:
All neurons in spinal cord gray matter have multipolar cell bodies. Based on axon destina-
tion, they can be divided into three major types, each of which has several subtypes:

1] Efferent neurons (embryologically derived from basal plate) send axons into the ventral root.
Cell bodies of efferent neurons are located in ventral horn (somatic efferents) or in intermediate
substance (visceral efferents).
• somatic efferent (SE) neurons:
alpha motor neurons— innervate ordinary skeletal muscle fibers (motor units);
gamma motor neurons—innervate intrafusal muscle fibers (within muscle spindles);
• visceral efferent (VE) neurons: preganglionic sympathetic and parasympathetic neurons.

2] Projection neurons send axons into spinal white matter to travel to the brain (or to a
distant part of the spinal cord). The axons form tracts associated with ascending spinal pathways that
have different functions.
Projection neurons may be categorized according to the types of stimulation that ultimately
excites them: Some projection neurons respond specifically to thermal or mechanical mild or noxious stimuli;
however, many projection neurons respond non-specifically to both mild and noxious stimuli (they function to maintain
alertness). Some projection neuron respond only to somatic stimuli (exteroceptors or proprioceptors); others respond to
both somatic and visceral stimuli. The latter are the basis for the phenomenon of referred pain.

3] Interneurons have axons that remain within spinal gray matter. Interneurons are inter-
posed between spinal input (from peripheral nerves or brain) and spinal output (efferent neurons).
By establishing local circuits, interneurons "hardwire" input to output and thus determine the inher-
ent reflex responses of the spinal cord (spinal reflexes).

Spinal Pathways
Primary Afferent Neuron = the first neuron in a spinal reflex or ascending spinal pathway.
Primary afferent
neurons have their Spinal Nerve
unipolar cell bodies in Spinal
spinal ganglia. Receptors Ganglion
are found at the periph- Primary Afferent Neuron
eral terminations of their
axons. Their axons Dorsal Root Collateral branches to spinal gray mater
traverse dorsal roots, Spinal Cord Cranial branch to brain
penetrate the spinal cord
(at the dorsolateral
sulcus) and bifurcate into
cranial and caudal
branches which extend
over several segments within white matter of the dorsal funiculus.
Collateral branches from the cranial and caudal branches enter the gray matter to synapse on
interneurons and projection neurons (or directly on efferent neurons for the myotatic reflex).
In some cases (discriminative touch), the cranial branches of incoming axons ascend directly
to the brainstem where they synapse on projection neurons of the pathway.

33
 Note: Pathway = sequence (chain) of neurons synaptically linked to convey
excitability changes from one site to another.

Ascending Pathways:
Chains of neurons carrying information from receptors to the brain (cerebral cortex).

Neuronal sequence:
Primary afferent neurons synapse on projection neurons typically located in spinal
gray matter. The axons of projection neurons join ascending tracts and synapse on neurons in
the brain. Ultimately, the pathway leads to thalamic neurons that project to the cerebral
cortex.

The function of a particular pathway is determined by: 1] which primary afferent neurons
synapse on the particular projection neurons of the pathway, and 2] where the projection
neurons synapse in the brain.

In general, pathways may be categorized into three broad functional types:

1] Conscious discrimination/localization (e.g., pricking pain, warmth, cold, discriminative
touch, kinesthesia) requires a specific ascending spinal pathway to the contralateral thalamus which,
in turn, sends an axonal projection to the cerebral cortex. Generally there are three neurons in the
conscious pathway and the axon of the projection neuron decussates and joins a contralateral tract
(see the first two pathways on the following page; the third pathway is the one exception to the general rule).

2] Affective related (emotional & alerting behavior) information involves ascending spinal
pathways to the brainstem. Projection neurons are non-specific. They receive synaptic input of
different modalities and signal an ongoing magnitude of sensory activity, but they cannot signal
where or what activity.

3] Subconscious sensory feedback for posture/movement control involves ascending spinal

pathways principally to the cerebellum or brainstem nuclei that project to the cerebellum. Generally
there are only two neurons in a subconscious pathway and the axon of the projection neuron joins an
ipsilateral tract (see the last pathway on the following page).

Descending Spinal Pathways:

Axons of brain projection neurons travel in descending tracts in spinal white matter. They
arise from various locations in the brain and synapse primarily on interneurons.

By synapsing on interneurons, descending tracts regulate:

1] spinal reflexes;
2] excitability of efferent neurons (for posture and movement); and
3] excitability of spinal projection neurons, i.e., the brain is able to regulate sensory
input to itself. In some cases, descending tracts affect axon terminals of primary afferent
neurons, blocking release of neurotransmitter (presynaptic inhibition).

34
 Ascending Pathway Examples

Discriminative Touch Spinal Pathway

Fasciculus gracilis
BRAIN Medial
Spinal Cord Nucleus gracilis
(dorsal view) lemniscus
midline to thalamus

Medial
Cuneate Nuc.
Fasciculus gracilis Fasciculus cuneatus

Pelvic limb neuron Thoracic limb neuron

Spinothalamic Pathway (pain & temperature)

Spinothalamic Tract
To
Dorsomarginal Nuc.
thalamus
midline

Spinal Cord BRAIN

Pelvic limb neuron Thoracic limb neuron

Spinocervicothalamic Pathway (touch and pain)

Spinal Cord
Dorsal horn Spinocervicothalamic Tract BRAIN
midline Medial
lemniscus
to thalamus
C-1,2

Lateral Cervical Nuc.

Pelvic limb neuron Thoracic limb neuron

Spinal Pathways for Proprioceptive Feedback to Cerebellum

Spinal Cord
Dorsal Spinocerebellar Tract BRAIN
Nucleus Thoracicus Fasciculus cuneatus Lateral
midline
L- 4 Cuneate Nuc.
T-1
Caudal
cerebellar
peduncle

Thoracic limb neuron

Pelvic limb neuron
35
Lecture 5

Spinal Reflexes &

Neuronal Integration
Reflex = an inherent, subconscious, relatively consistent responses to a particular stimulation.

Reflexes may be categorized as:

somatic (involving skeletal m.) or autonomic (impacting viscera); and as
brainstem (involving cranial nn.) or spinal (involving spinal nn. and the spinal cord)

In contrast . . .
Reaction = an inherent, subconscious, relatively consistent responses to a particular stimula-
tion, involving the cerebellum and cerebral cortex; e.g., hopping reaction & tactile placing reaction.

Examples of brainstem reflexes include:

— eyelids close when the cornea is touched (corneal reflex)
— lip moves in response to a noxious stimulation (pin prick)

Examples of spinal reflexes, involving spinal nerves and the spinal cord, include:
— extensor thrust: paw proprioceptors trigger lib extension
— panniculus reflex: pricking skin triggers contraction of cutaneus trunci m.
— myotatic reflex: muscle stretch is resisted by contraction of the muscle
— withdrawal reflex: limb is withdrawn from a noxious stimulus

NOTE:
Reflex responses are determined by interneurons which “hard-wire” afferent input to efferent
output. Interneurons organize efferent neurons (motor units) into meaningful movement components,
which can be utilized by either spinal input or descending pathways.
Since "voluntary movement" and "involuntary reflex/reaction" compete for control of the
same interneurons circuits, they cannot be independent on one another. Thus, brain activity will
influence spinal reflex responses, making reflex evaluation an interpretive art.

Withdrawal Reflex = Flexor (Crossed Extensor) Reflex

Features of the reflex (diagrammed on the next page) include . . .

— primary afferent neuron (1) participates in both reflexes (2) and ascending pathways (3);
— divergent interneuronal circuit propagates to several segments and right and left sides;
— positive feedback prolongs the reflex beyond the time of the stimulus (A);
— individual interneurons are either excitatory or inhibitory (black cells) in their effect;
— antagonists are inhibited while agonists are excited (reciprocal
reciprocal innervation) (D);
— descending pathways (C) modify reflex circuit (reflex is not independent of brain control).

NOTE: As the reflex is tested clinically, the crossed extension component disappears after
the first 3 weeks of age as descending pathways mature; but later in life, the nor-
mally inhibited crossed extension reappears if “upstream” damage to descending
fibers removes the inhibition.
36
 Withdrawal Reflex
1
DL Sulcus
3 DL F.

A
C

D D

flexor
flexor

extensor
extensor

BACKGROUND PROPRIOCEPTIVE INFORMATION

Proprioceptors are mechanoreceptors, located in muscles/tendons & joint capsules/ligaments.

Proprioceptors provide:
• subconscious feedback about the status of muscles & joints,
• conscious kinesthesia (sense of position & movement), and
• pain

Joint receptors:
• free nerve endings that respond to extreme movement or inflammation (pain)
• encapsulated receptors:
— tonic: signal joint position
— phasic: respond to rate of change in joint position (largely subconscious)

Muscle & tendon receptors:

free nerve endings:
endings pain
(Golgi) tendon organs:
organs located in series with muscle fibers (tension detector)
muscle spindles:
spindles located in muscle belly (length detector)
37
 Muscle Spindle and Myotatic Reflex
Muscle spindles are:
• elaborate proprioceptors positioned in Types of nerve fibers
parallel with muscle fibers; found in a muscle nerve
• designed to signal muscle length.

Morphologically, a muscle spindle consists

of a connective tissue capsule enclosing:
— two kinds of mechanoreceptors,
— two kinds of intrafusal muscle fibers,
— two kinds of gamma efferent neurons.

Intrafusal muscle fibers:

vs. extrafusal (typical) muscle fibers
• very small, anchored in endomysium
• do not contribute anything to whole
muscle tension
• center of each fiber is packed with
nuclei & lacks myofilaments
• polar regions are striated and
innervated by gamma neurons
• two kinds of intrafusal muscle fibers:
nuclear bag fibers — central region
is dilated; fiber extends beyond the capsule;
nuclear chain fibers — smaller,
central region contains chain of nuclei.
Muscle & Tendon Receptors
Mechanoreceptors within muscle spindle :
They are activated by stretch of the central region, which is stretched either
1) by contraction of polar regions of intrafusal muscle fibers, or
2) by passive stretch of the whole muscle (including the intrafusal fibers)

1] primary (annulospiral) endings — spiral around central (nuclear) regions;

they are endings of large nerve fibers (type IA);
initially AP frequency reflects rate of stretch; then
steady AP frequency reflects degree of stretch

2] secondary endings — "flower-spray" formations adjacent to nuclear chain regions;

they are endings of type II nerve fibers;
AP frequency is proportional to degree of stretch.

38
 tendon Myotatic Reflex

a
II
reticulo-
spinal tract
from brain

GAMMA
neurons
s
en ding
e
p l at
en d
n dings
le
tr ai

ALPHA neurons
same muscle
antagonist muscle
extrafusal
muscle fiber
Myotatic Reflex
Clinically, a myotatic reflex is elicited by abruptly tapping a tendon (e.g., the patellar tendon).
Suddenly deforming/displacing a tendon effectively stretches the associated muscle.
When a whole muscle is suddenly stretched (as a result of tendon deformation), annulospiral
receptors in muscle spindles are simultaneously excited, triggering a volley of action potentials in
IA afferent axons. Within the CNS, the axons activate excitatory synapses on alpha motor neurons
that innervate the muscle that was stretched. Also, alpha motor neurons to antagonistic muscles are
inhibited via interneurons. As a result, the stretched muscle immediately contracts.
Thus, the myotatic reflex functions to oppose muscle stretch. Since interneurons are
by-passed in eliciting the contraction, the response is rapid, localized, and relatively resistant to hy-
poxia, fatigue, drugs, etc.

39
Reflex sensitivity:
Sensitivity of the myotatic reflex (the extent to which a muscle can be stretched before it re-
flexly contracts) is determined ultimately by the contractile state of the polar regions of the intrafusal
muscle fibers—because the degree of contraction of the polar regions determines the pre-existing
bias (degree of stretch of intrafusal central regions) when the whole muscle is stretched.
Thus, since gamma neurons innervate intrafusal polar regions, sensitivity of the myotatic
reflex is set by the frequency of AP's in axons of gamma neurons, and gamma neuron excitability
is controlled by descending tracts from the hindbrain (reticulospinal tracts & vestibulospinal tracts).

Functions of the myotatic reflex:

• Muscle tone = the resistance muscles offer when being stretched (lengthened)
= the resistance encountered when an appendage is manipulated

— tone is set by: brain ——> descending pathways ——> gamma neuron firing rate
— normal tone is variable, but appropriate to the animal’s current behavioral state

vs. hypertonia (spasticity) = fixed excessive tone, i.e., excess resistance to manipulation
— due to excessive gamma neuron excitation (rate of firing)

or hypotonia ("weakness") = fixed deficient tone, e.g., “rag-doll” appendages

— the result of insufficient gamma neuron excitation.

• Posture maintenance under changing conditions of load & fatigue

By using myotatic reflexes, the brain is able to set muscle lengths and fix joint position (i.e.,
posture) without concern for load and fatigue. The brain sets lengths of intrafusal muscle fibers to
correspond to desired whole-muscle lengths.
Any muscle that is longer than the desired length will have its spindle receptors activated and
the resultant myotatic reflex will persist until the muscle has shortened to the proper length. After
posture is set, motor neurons will receive a burst of excitatory synaptic input whenever a muscle
becomes stretched and they will lose that excitation once the muscle shortens sufficiently.
By analogy, this is a servosystem, e.g., one sets a thermostat [the brain sets gamma neuron
excitation] to control a furnace [myotatic reflex] to maintain a desired temperature [posture].

• Voluntary movement
For slow movements, posture can be sequentially adjusted to produce movement, e.g.,
hindlimb scratching the flank; learning any new movement sequence; etc. For abrupt voluntary
movements, the brain co-activates alpha & gamma neurons to maintain spindle sensitivity while
muscles shorten (spindles fire during movement). Gamma neurons (myotatic reflexes) must be inhib-
ited in antagonistic muscles as agonists are excited.

Clinical Considerations
A clinician taps a tendon in order to :
1) verify the integrity of local peripheral nerves and spinal cord segments; and
2) evaluate brain control and the integrity of descending tracts
— looking particularly for evidence of fixed hypertonia or hypotonia.
40
 Neuronal Integration
A typical multipolar neuron in the CNS receives many thousands of synaptic inputs (excitatory/
inhibitory; axosomatic/axodendritic; from interneurons/projection neurons; etc.).
How does a neuron integrate all
of its diverse synaptic input? How does it make "sense" of the diversity and "fire" appropriately to
effectively influence other neurons in its circuit? The answer — neuronal integrtion.

Synaptic inputs — predominantly on dendrites & soma (receptive zone):

axosomatic excitatory synapses — depolarize entire soma (cell body) surface. The
cell body acts like a sphere (charges/ions distribute evenly over a spherical surface).
Although each EPSP affects the whole soma, a single EPSP has a very limited effect.
axodendritic excitatory synapses — depolarize preferentially toward the soma. The EPSP is
passively conducted toward a lower resistance (asymmetrical diameter = asymmetrical resistance).

NOTE:
Inhibitory synapses behave like excitatory ones,
except that they produce IPSPs that hyperpolarize
the soma and cancel EPSPs).

Neuronal output:
• an action potential (AP) originates at the initial segment of the axon where high density of
voltage-gated Na+ channels are present;
• the initial segment is greatly influenced by the massive soma adjacent to it, i.e., the soma
continually depolarizes or hyperpolarizes the initial segment at each instant of time;
• whenever the initial segment reaches threshold depolarization, it generates an AP that
travels along the entire axon.

Thus, the soma membrane of each neuron integrates total syn-

aptic input at each moment of time! Integration is the result of
algebraic summation of synaptic activity (EPSPs and IPSPs). The
floating soma membrane potential reflects the net excitatory and
inhibitory synaptic input to a particular neuron at a particular time.

The magnitude of soma depolarization (an analog signal ideal for integration)
is converted to frequency of APs along the axon (a digital signal ideal for
distance conduction).

Factors influencing synaptic effectiveness:

• for a given competing input source, impact on a target neuron depends on:
1) number of source synapses on the target neuron;
2) locations of source synapses on the target neuron.
• for an individual synapse, effectiveness is related to synaptic location on the target neuron
most effective {axon hillock >> soma >> proximal dendrite >> distal dendrite} least effective
• a given amount of synaptic input will have more effect in a small (vs. large) neuron cell body;
thus, within a neuronal pool, small neurons are recruited first, large neurons last.

41
 • synaptic effect is increased by repetitive firing (temporal summation);

• synaptic effect is increased by collaborative firing of different sources (spatial summation).

Temporal summation: repeated synaptic input can sum to produce an increased effect, when
subsequent PSPs arrive before previous PSPs completely decay.

Spatial summation: synaptic input from a second source can sum with that of a primary source to
produce an increased effect.

42
 6

4 5
3
1

triceps
brachii m.

Neuronal Integration Scenario

Final common pathway neuron
anatomically = ventral horn neuron or neuron cranial nerve motor nucleus
electrophysiologically = alpha motor neuron
clinically = lower motor neuron (as opposed to upper motor neuron)
A final common pathway (FCP) neuron innervates skeletal muscle. The neuron and the skeletal muscle fibers it
innervates constitute a motor unit. The nervous system controls skeletal muscles by controlling FCP neurons.
A given FCP neuron receives thousands of synapses, mostly from interneurons. Some of the inputs are excitatory,
others are inhibitory. Some of the input originates in the brain, other from receptors and primary afferent neurons. Some
of the sources of input have a major effect on the neuron, other inputs provide merely background excitation.

Typical inputs to a FCP motor neuron innervating an extensor muscle:

Background excitation — (axodendritic synapses; merely predispose neurons to fire)
1. reticulospinal axons = muscle activity for standing
2. vestibulospinal tract = balance and muscle activity for standing
3. propriospinal axons = intersegmental reflexes
Major excitatory inputs — (axosomatic synapses; excite neurons to fire APs)
4. commissural interneurons = crossed-extensor reflex
5. rubrospinal tract = voluntary movement
6. primary muscle spindle afferent axon (IA) = stretch (myotatic) reflex
Inhibitory inputs — (inhibitory axodendritic or axosomatic synapses; cancel excitatory synapses)
7. pain afferent axon = inhibits extensor muscles
8. pyramidal tract axon = controls distal muscles (inhibits extensor muscles)

Clinical note: Damage to FCP neurons (or axons in peripheral nerves) results in flaccid paralysis
of skeletal muscles (neither voluntary movement nor reflex activity is present).
43
Lecture 6

Cranial Nerves
Overall Objectives: To understand the organization of cranial nerves with respect to
their nuclei within the brain, their course through and exit from the brain, and
their functional roles.

I. Factors Responsible for Complex Internal Organization of Brain Stem:

1. Development of the Fourth Ventricle
a) Medulla Oblongata and Pons are ventral to the fourth ventricle
b) Alar Plate is displaced lateral to Basal Plate.

2. Cranial nerve nuclei form discontinuous cell columns rather than

continuous cell columns as seen in the spinal cord.

3. Some cranial nerve nuclei migrate from their primitive embryonic positions
(e.g., nuclei of nerves V & VII).

4. Special senses (hearing, balance, taste and vision) develop in association with the
brain stem (SVA & SSA).

5. Development of the cerebellum and its connections adds additional components.

Schematic Diagram of the developing brainstem, showing how the development

of the fourth ventricle displaces the alar plates lateral to the basal plates.

II. Cranial Nerve Nuclei:

A nucleus is a profile of a column of neuron cell bodies. Efferent nuclei are composed of cell
bodies of alpha or gamma motor neurons (SE) or preganglionic parasympathetic neurons (VE).
Afferent nuclei consist of cell bodies of projection neurons and interneurons upon which primary
afferent axons synapse in connection with ascending pathways or reflex axctivity.

44
III. Motor Efferent Nuclei (Basal Plate Derivatives):

1. SE (Somatic Efferent) Nuclei: SE neurons form two longitudinally oriented but discon-
tinuous columns of cell bodies in the brain stem. The neurons that comprise these columns are
responsible for innervating all of the skeletal musculature of the head. Refer to the diagram on page
46 for the location of brain stem nuclear columns.

A) Oculomotor, Trochlear, Abducent and Hypoglossal Nuclei — are formed by a column

of cells located near the dorsal midline of the brainstem. The nuclei innervate muscles of the tongue
and eye which are derived from somites. Damage or lesions to these nuclei or their nerves (III, IV,
VI, and XII) result in the following clinical signs:

1) Oculomotor, trochlear or abducent (cranial nerves III, IV, &VI): Abnormalities

in eye movement, deviation of the eyes (strabismus).

2) Hypoglossal (XII): Paralysis and atrophy of tongue muscles; deviation of

tongue toward the side of damage, problems chewing & swallowing.

Afferent and Efferent Nuclei

GVA GSA
IV
alar GSA VE
plate GVA SE
VE
basal SE (SVE)
plate SE
olivary
nucl.

spinal cord brain stem

Comparison of the four major cell columns in the spinal cord with the more complicated
picture seen in the brainstem. Note that the adult location of the alar derivatives (sensory
nuclei) is located laterally in the brainstem instead of dorsally as it is in the spinal cord.

B) Motor Nucleus of the Trigeminal N. (cranial nerve V), Facial Nucleus (cranial nerve
VII) and Nucleus Ambiguus (cranial nerves IX & X)— are formed by a column of cells located in
the ventrolateral brainstem. This location results from the ventrolateral migration of the cell column
during development. These neurons innervate muscles derived from somitomeres in pharyngeal
arches. (Formerly this cell column was regarded as (SVE)).
Damage or lesions involving these nuclei or their nerves result in the following clinical signs:

1) Motor nucleus of the Trigeminal N.: innervates muscles of mastication and

damage to it or the trigeminal nerve results in paralysis of these muscles
and associated muscle atrophy (bilateral damage results in dropped jaw).

45
 2) Facial nucleus: Innervates muscles of facial expression (ears, eyelids, nose
& lips); damage to the nucleus or facial nerve results in facial paralysis.

3) Nucleus Ambiguus: innervates muscles of the soft palate, larynx, and

pharynx (involved with speech, coughing, swallowing & gag
reflexes); damage results in swallowing and vocalization difficulties.

2. VE (Visceral Efferent) Nuclei: Represent the cranial portion of the parasympathetic

division of the autonomic nervous system (preganglionic parasympathetic neurons). Four nuclei are
recognized, but only two are important to remember: the parasympathetic nucleus of the vagus
nerve and the parasympathetic nucleus of the oculomotor nerve.
The parasympathetic nucleus of the vagus innervates cervical, thoracic and abdominal
viscera while the parasympathetic nucleus of III innervates pupillary constrictor muscle and the
ciliary body muscle of the eye:
1) Parasympathetic nucleus of III — damage causes loss of pupillary
contriction in response to light in the eye on the side of the lesion.

2) Parasympathetic nucleus of X — damage results in accelerated heart rate,

increased blood pressure, and disturbances of gastrointestinal activity.

IV. Sensory Afferent Nuclei (Alar Plate derivatives):

1. GSA (General Somatic Afferent) Nuclei: Represented by the sensory trigeminal com-
plex which is located quite laterally in the brain stem. The complex is composed of the following
three major subdivisions:

a) Nucleus of the spinal trigeminal tract (spinal trigeminal nucleus)—located in the

medulla; associated predominately with pain and temperature sensation from the face and oral
cavity; damage to this nucleus results in loss of pain and temperature sensation from half the face.

b) Pontine nucleus of the trigeminal nerve (principal sensory nucleus)—located in

the pons; associated with touch and pressure sensation from the face and oral cavity; damage result
in loss of touch and pressure sensation from the face.

c) Mesencephalic nucleus of the trigeminal nerve: located in the midbrain, receives

proprioceptive information from the face.

46
 2. GVA(General Visceral Afferent) Nucleus: Located lateral to the GVE column and
comprised of a single nucleus termed the nucleus of the solitary tract (nucleus solitarius). The GVA
portion of this nucleus is associated with cranial nerves IX and X. It mediates visceral sensation from
the pharnyx, larynx and portions of the esophagus.

3. SVA (Special Visceral Afferent) Nuclei:

A. There is a taste SVA component in the nucleus of the solitary tract. Taste is associ-
ated with cranial nerves VII, IX and X which convey taste from the tongue and pharynx. Lesions or
damage to the nucleus solitarius will disrupt taste sensation.

B. The olfactory nerve is associated with olfactory SVA sensation. This nerve how-
ever is not foundf in the brainstem; rather, olfaction is conducted directly to the piriform lobe of the
telencephalon. Lesions or damage to the olfactory nerve will interrupt olfaction.

4. SSA (Special Somatic Afferent) Nuclei: These brain stem nuclei relate to the sense of
vision (lateral geniculate nucleus), the sense of hearing (cochlear nuclei) and the ability to maintain
balance (vestibular nuclei).
The medullary SSA column related to hearing and balance is located dorsally and laterally in
the brain stem and is related to cranial nerve VIII.
The SSA nucleus related to vision is located in the thalamus and is associated with the optic
nerve/tract input. Obviously damage to cranial nerves II or VIII or their associated nuclei will have
profound effects on the animal’s ability to see or hear, respectively.

Cranial Nerve inner ear

(SSA)
Cell Columns
skin
Diagram indicating the nuclear columns in f (GSA)
af
.

the brain stem and illustrating the type of t ic

ma
so
ff
la

structures supplied by the different catego-

ff

ra
eff
le

ce taste
ra

ries and the nerves containing fibers from i s

ati c

v (SVA)
ce
v is

the different nuclear columns.

som

(GVA)

visceral
somatic efferent
efferent

47
 Sensory (left) and Motor (right) Cranial Nerve Nuclei
rostral m
colliculus tectu

III
ventricle
genu VII
V
po VI
ns VII
olivary nucl.
facial nerve

optic
chiasma

le
su
crus cerebri

ap
al c
inte
rn thalamus

p.III
III
pons
n.mes.tr.V
genu VII
IV
mes.tr.V

n.pon.sen.V motorV

dorsal nucl.
trapezoid body
vestibular VI
nucl. p.VII VII
p.IX
n.sp.tr.V
p.X
sp.tr.V n.amb.
XII

n.sol.tr.

XI

olivary nucl.

48
Cranial Nerves and Their Functions:

Name and Brain Region Function Clinical Symptom Seen

Number Associated (Functional Examination After Injury
With Components)
Olfactory - I Cerebrum Smell (SVA) Owner’s Anosmia
Observations (Loss of Smell)

Optic - II Diencephalon Vision (SSA) Menace Response Anopsia

(Loss of Vision)

Oculomotor - III Midbrain Eye Movement Horizontal Eye Strabismus: eye

(SE, VE) Movement; Pupil- deviated down &
lary Light Reflex out. Large Pupil
Trochlear - IV Midbrain Eye Movement Extend head and Cat: dorsal aspect
(Dorsal Oblique look for dorso- of vertical pupil
Muscle: SE) lateral strabismus deviated laterally
Trigeminal - V Pons Masticatory Move- Jaw movement Bilateral damage =
Ments, sensation Eye blink reflex Dropped jaw,
From face (SE, Asymmetric
GSA) chewing, atrophy
Abducens - VI Medulla Eye Movement Lateral Eye Double vision;
(Lateral Rectus Movement Strabismus: eye
Muscle; SE) deviated medially
Facial - VII Medulla Facial Movement; Facial Movement Facial paralysis,
Taste, rost. tongue drooling
(SE, SVA, VE)
Vestibulocochlear Medulla Hearing and Horizontal and Deafness,
- VIII Balance (SSA) Vertical Eye Head tilt,
Movement nystagmus
Glossopharyngeal Medulla Tongue and Pharyngeal gag Choking,
- IX Pharynx (GVA, reflexes Swallowing
VE, SVA) Difficulty
Vagus - X Medulla Pharynx, Larynx, Gag reflexes, Hoarseness,
Heart, Viscera Blood Pressure, Inspiratory
(SE, VE, GVA ...) Heart Rate dyspnea
Spinal Accessory Medulla Trapezius, + three. Neck movement Weakened
- XI neck mm. (SE) turning of neck

Hypoglossal - XII Medulla Tongue Muscles Tongue Deviation of

(SE) movement Tongue toward
Side of lesion

49
Lecture 7

Vestibular System
Introduction:
The vestibular system is responsible for maintaining normal position of the eyes and head as
external forces tend to displace the head from its “normal” position. Located within the inner ear, the
vestibular apparatus is the sense organ that detects linear and angular accelerations of the head and
relays this information to brainstem nuclei that elicit appropriate postural and ocular responses.
Note: Because [force = mass • acceleration ] and because head mass is constant, detecting head
acceleration is equivalent to detecting external force to the head.

Inner Ear Anatomy:

The inner ear is called the labyrinth because it consists of channels and chambers hollowed
out within the temporal bone. The labyrinth has osseous and membranous components:

Osseous Labyrinth — tubes and chambers in the petrous part of the temporal bone that
contain perilymph fluid and house the membranous labyrinth. The three osseous components are:

1) Cochlea — a spiral chamber that is related to hearing and will be discussed later

2) Vestibule — a large chamber adjacent to the middle ear

3) Semicircular Canals — three semicircular channels in bone, each semicircular

canal is orthogonal to the other two

bone
perilymph fluid cupula
membrane
memb. labyrinth
endolymph fluid
BONE
otolith memb.
macula

UTRICLE
crista
ampularis semicircular
duct
Schematic diagram of the osseous labyrinth containing the membranous labyrinth. The
vestibule relationship (left) and the semicircular canal relationship (right) are shown.

Membranous Labyrinth — consists of interconnected tubes and sacs that are filled with
endolymph, a fluid high in potassium. (Fluid outside the membranous labyrinth is perilymph, which
is low in potassium and high in sodium like typical extracellular fluids.)

50
 The membranous labyrinth, which contains
the sense organ receptor cells, consists of the follow-
ing components:
1) Cochlear Duct — related to hearing (will
be discussed later). Ducts
2) Utricle — larger of two sacs located in the
vestibule
3) Saccule — smaller of two sacs located in
the vestibule
4) 3 Semicircular Ducts — each duct is
located within one of the semicircular canals. Each
duct has a terminal enlargement called an ampulla
which contains a crista ampullaris, a small crest
bearing sensory receptor cells.

Vestibular Apparatus:

Vestibular apparatus is a collective term for sensory areas within the membranous labrinth
responsible for detecting linear acceleration (e.g., gravity) and angular acceleration of the head.

The vestibular apparatus consists of:

1) macula of the utricle — the sensory area (spot) located in the wall of the utricle; it is
horizontally oriented and detects linear acceleration in the horizontal plane (side to side).

2) macula of the saccule — the sensory spot in the wall of the saccule; it detects linear
acceleration in the vertical plane (up and down).

3) crista ampullaris — one per semicircular duct ampulla; each detects angular acceleration
directed along the plane of the duct.

kinocilium

otolith membrane

vestibular
ganglion vestibular
nerve
efferent
CNS
bipolar

Schematic illustraion of a macula, including neurons of the vestibular nerve. Two types
of receptor (hair) cells have stereocilia that extend into the overlying otolith membrane.

51
Signal Transduction:
kinocilia
All components of the vestibular appa-
ratus (each macula & crista ampullaris) have + +
++
+
the same kind of sensory epithelium, composed stereocilia

of supporting cells and receptor (hair) cells. tip-link

From the apical surface of each hair cell,

stereocilia protrude into an overlaying mem-
branes.
hair cell
Membrane movement results in deflec-
tion of stereocilia. Deflection toward the
kinocilium mechanically opens ion channels.
This allows potassium ions to flow from the
endolymph into the hair cell thus depolarizing
the receptor cell membrane.
This depolarization (receptor potential) Rate of firing — vestibular nerve axon
cause release of glutamate from the basolateral
cell membrane of the receptor cell. The
gluatamate neurotransmitter triggers action time
potentials in afferent axons of the vestibular resting state (tonically active)
nerve.
Deflection away from the kinocilium
closes ion channels and reduces glutamate one Action Potential

release.

Crista Ampullaris. Stereocilia are on off

depolarized stimulus
embedded in a gelatinous membrane called a
cupula. The cupula is moved by fluid inertia
when the head rotates in the plane of a semicir-
cular duct. The direction of head rotation is
indicated by the relative amount of activity
from the three semicircular ducts.
hyperpolarized on off
stimulus
receptor (hair) cell
Macula. Stereocilia are embedded in a
gelatinous membrane termed the otolith mem-
brane because it contains calcium concretions (“ear stones”). Being denser than surrounding en-
dolymph, the otolith membrane has more inertia than the fluid and it lags during linear acceleration
or deceleration of the head.

Notes:
1) Receptor cells are spontaneously active and vestibular nerve axons continually conduct
action potentials to the brainstem. Thus, movement of sterocilia results in an ncrease
or decrease in the rate of spontaneous activity.

2) Vestibular organs of each side are mirror images, a shift toward the kinocilia on one
side results in a shift away from the kinocilia on the other side. Thus, spontaeous
activity, which is bilaterally balanced under normal postural conditions, is quickly
imbalanced during head acceleration.
52
CNS Connections:
Vestibular nerve fibers (axons from neuron cell bodies of the vestibular ganglion) travel from
the inner ear to the brain. They synapse in vestibular nuclei of the brainstem and in the nodulus
or flocculus of the cerebellum.

Vestibular nuclei:
Four vestibular nuclei are located bilaterally in the medulla oblongata and pons. They receive
input from the vestibular nerve and project to:
1) cerebellum,
2) reticular formation,
3) spinal cord via the lateral vestibulospinal tract (which activates limb extensor
muscles via alpha and gamma neurons), and
4) neurons controlling eye (3, 4, and 6 cranial nerves) and neck (cervical spinal cord)
muscles via the medial longitudinal fasciculus.

rostral lateral caudal

(descending)

medial
Four Vestibular Nuclei
(lateral view)

thalamus
III oculomotor

IV trochlear

VI abducent

cerebellar rostral
peduncles
medial lateral

caudal

lateral vestibulospinal
tract
reticulospinal tracts
medial longitudinal fasiculus
(mlf)
Spinal Cord
53
Vestibular Reflexes:

Effects on Eyes:
The eyes are shifted in a direction opposite to the direction that the head is accelerated, in
order to maintain a stable visual field.
For example, head rotation to the right produces increased AP frequency in the right vestibu-
lar nerve and decreased frequency in the left. Vestibular nuclei on the right side dominate activity in
the left abducens nucleus & right oculomotor nucleus, causing the eyes to move to the left.
In general, vestibular nuclei push the eyes contralaterally. When nuclear activity is balanced
on each side the push is balanced and eyes are not shifted.

Effects on Neck and Limbs:

Analogous to eye control, the head is maintained in a normal posture by means of vestibular
reflex control of neck muscles.
Vestibular nuclei influence extensor muscles in the limbs; extensor muscles are contracted on
the side toward which the head is accelerating (to preclude falling).

Clinical considerations:
Lesions affecting the middle ear, vestibular apparatus, vestibular nerve, or vestibular nuclei
are common. Such lesions produce imbalanced neural activity which leads to a vestibular
syndrome.

Vestibular syndrome: (you should be capable of diagnosing which side is lesioned)

• head tilt — lesion is on the “down ear” side

• stumbling, falling, rolling — direction is toward the lesion side

• nystagmus (oscillatory eye movement — abnormal when the animal is not rotating)
— slow phase of nystagmus is directed toward the side of the lesion

Note: The normal (undamaged) side is more active than the lesioned (damaged) side. This
imbalance causes reflexes to be expressed as if there were an “acceleration” toward the
normal side. (During balanced vestibular activity, bilateral reflex effects cancel).

Nystagmus = eyes continuously shift: slowly to one side, then quickly back to center.

• vestibular nystagmus — is generated reflexly by vestibular nuclei in response to

angular acceleration;

• opticokinetic nystagmus — is generated by cerebral cortex when focusing on

moving objects, e.g., train passenger focussing on
telephone poles.

54
Lecture 8

Posture & Movement

In veterinary neurology, abnormalities of posture & movement are more important than sensory
disorders because animals readilty express motor behavior but hardly at all report their feelings.

Preview: Posture/Movement Hierarchy

Spinal Cord and Cranial Nerve Motor Nuclei
Local reflex—useful response to a stimulus (determined by local interneuronal circuits).

Hindbrain
Standing posture—excitation of alpha & gamma motor units of extensor muscles
(driven by spontaneous activity of reticular formation & vestibular neurons).
Equilibrium—maintaining normal position of eyes, head, & body (vestibular system).

Midbrain
Orientation—orienting head/eyes/ears toward abrupt visual/auditory stimuli (tectum).
Specific movements—moving individual joints (via red nucleus and rubrospinal tract).

Forebrain
Inherent movement sequences—species-specific patterns of posture/movement/gait
(basal nuclei interacting with thalamus & motor areas of cerebral cortex).
Learned movements—including learned movement sequences performed too rapidly
for sensory feedback (involves premotor cerebral cortex).

Brain Structures Concerned with Posture & Movement

----------------------------------------------------------------------------------------------------------- Hindbrain
Reticular Formation
Anatomy: network (mixture) of gray & white matter, found throughout the brainstem
— synaptic input from collateral branches of ascending tracts (e.g., spinothalamic tract)

Physiology: spontaneously active neuronal circuits; perform three major functions:

— ascending system to alert cerebral cortex (via non-specific thalamic nuclei) vs. coma
— vegetative centers: regulate heart rate, respiration, digestion, micturition, etc.
— standing posture and muscle tone via pathways to alpha & gamma neurons:
two divisions — the lateral one is spontaneously active & dominant:
1} located laterally in pons & medulla: pontine reticulospinal tract —
activates alpha & gamma motor units of extensor muscles
2} located medially in medulla: medullary reticulospinal tract —
inhibits neurons to extensor mm. & excites neurons to flexor mm.;
not spontaneously active — driven by cerebral cortex

Vestibular nuclei discussed previously

Two descending tracts: lateral vestibulospinal tract— which also drives standing posture, &
medial vestibulospinal tract (m.l.f.)— which controls neck muscles.
Vestibular nuclei also utilize the two reticulospinal tracts to adjust muscle tone.

55
-------------------------------------------------------------------------------------------------------------Midbrain
Red nucleus
The nucleus gives rise to the rubrospinal tract—the principal descending tract for voluntary
movement in domestic animals. (Rubrobulbar fibers go to cranial nerve motor nuclei.)
The red nucleus is merely a collection of projection neurons. Axons from the motor area of
cerebral cortex synapse on neurons of the red nucleus and control their activity.
The rubrospinal tract decussates in the midbrain and descends in the dorsal half of the lateral
funiculus. Rubrospinal fibers synapse on spinal interneurons and produce independent movements of
shoulder/hip; elbow/stifle; and carpus/hock (not digits).

Tectum (tectum = roof of the midbrain)

Rostral & caudal colliculi give rise to two tracts (which arise from rostral colliculus):
1} tectospinal fibers—descend to the cervical spinal cord (head turning);
2} tectobulbar fibers—to cranial nerve nuclei that control ear & eye movement.

Substantia nigra
Functions like a basal nucleus (see below). It has reciprocal connections with the striate body (caudate &
putamen), where its telodendria release the neurotransmitter dopamine. Deficiency of dopamine in primates
results in Parkinson's Disease (hypokinesia, rigidity, tremor).

------------------------------------------------------------------------------------------------------------Forebrain
Subthalamus
Functions like a basal nucleus (see below). It play a role in producing rhythmic movements such as are employed in
locomotion. In primates, lesions (damage) to subthalamus result in involuntary release of large flailing movements
(hemiballismus).

Basal nuclei
Three basal nuclei (caudate, putamen, & pallidum or globus pallidus) are associated with move-
ment. The nuclei do not give rise to descending tracts. Instead they participate in forebrain circuits in
which they communicate with cerebral cortex via thalamic nuclei.
Damage to basal nuclei impairs coordinated movement by affecting the magnitude, timing and
sequencing of individual components of a movement. (In domestic animals, lesions of the basal
nuclei usually result in circling to the affected side.)

Anatomically, the term "Basal Nuclei"

refers to non-cortical gray matter of the
telencephalon. There are five major nuclei (and
several smaller ones). Caudate Striate
The major nuclei can be anatomically
subgrouped in different ways: Body
1] Striate body (gray matter connecting Lentiform Putamen
caudate & putamen produce striations in the Nucleus
intervening internal capsule). Globus Pallidus
2] Lentiform nucleus (the putamen and
globus pallidus together have the shape (form)
of a lens.
Amygdaloid

Physiologically, only caudate, putamen, Claustrum

and globus pallidus play a motor role.

56
 Functionally, basal nuclei are involved in two separate circuits:
one, involving the caudate nucleus, is active in selecting & assembling movements;
the other, involving putamen, regulates amplitudes & durations of movement components.
Note: Caudate nucleus & putamen both inhibit globus pallidus which, in turn, inhibits
thalamic neurons that project to motor related areas of cerebral cortex.

Cerebral cortex
Motor-related areas of cerebral cortex:
• motor area—located around the cruciate sulcus; principal source of output for all voluntary
movement; it's the main source of two descending pathway systems (below)
• premotor area—located in frontal lobe rostral to the motor area; required for re-calling
learned, rapid-sequence movements (particularly involving distal muscles).
• supplementary motor area—located medial to premotor area; active when thinking
about a proposed movement; projects to motor area

Descending pathways for voluntary movement fall into two categories:

1] Pyramidal tract = a direct connection from primary and other motor areas of cerebral cortex to
efferent neurons, generally via local interneurons. Axons travel in the pyramid of the medulla oblon-
gata. Most axons decussate at the medullary-spinal junction (lateral corticospinal tract); some cross
at the level of termination in the cord (ventral corticospinal tract). The tract controls particularly
musculature of the manus and pes. It is concerned with fine (vs. coarse), precise movements.
Some corticospinal axons affect projection neurons of ascending pathways to enable the cerebral cortex to modify
sensory traffic on its way to the thalamus and cortex. The axons come from sensory areas of the cortex.

2] Extrapyramidal tracts = all other voluntary movement tracts directed by the cerebral cortex
(motor area). The tracts control proximal musculature and thus direct relatively coarse components
of posture/movement/locomotion. Naturally, this system is most important in domestic animals. The
principal tracts are: rubrospinal tract, pontine reticulospinal tract, and medullary reticulospinal tract.

Voluntary movement:
Urge —> Decision —> Selection (what) —> Execution (how)
[limbic system] [association neocortex] [premotor & caudate] [motor & putamem]

Veterinary Clinical Considerations:

Upper Motor Neuron Damage:
Loss of only pyramidal tract: paresis (partial paralysis or weakness) of manus & pes; inability to move digits
and lips independently & rapidly; loss of tactile placing.
Loss of motor cortex: disappearance of learned movement skills; spastic paralysis (absence of voluntary
movement capability, plus release of the pontine reticular formation).
Loss of whole forebrain (= midbrain animal): persistent standing posture but exhibits phasic actions (crouching,
stepping, etc.) if prodded to do so; capable of maintaining standing posture (righting reactions are intact).
Loss of forebrain & midbrain (= hindbrain animal): limbs rigidly extended constantly in a "saw-horse" attitude
(decerebrate rigidity); no locomotion or righting capability; tonic neck reflexes present (postural adjustments initiated by
neck proprioceptors).
Loss of whole brain (= spinal animal): temporary areflexia is possible with abrupt injury (spinal shock);
paralysis without spasticity; local spinal reflexes intact; crossed extension accompanies the withdrawal reflex.

Lower Motor Neuron Damage:

Spinal cord or peripheral nerve damage: paralysis and areflexia (flaccid paralysis); denerva-
tion atrophy of skeletal muscles with time.
57
 Movement Initiation Schema
Voluntary Movement

Globus
pallidus Descending Tracts:
Pyramidal tract:
Caudate = lateral & ventral
Thalamus and corticospinal tracts.
Purpose
Limbic Drive
Putamen Extra-pyramidal tracts:
1 = Rubrospinal tract
& 2 &`2 = Reticulospinal tracts
Association Neocortex
Reflex tracts:
3 = lateral vestibulospinal tract
4 = medial vestibulospinal tract
5 = tectospinal fibers

Motor-related
NOTE:
Neocortex Substantia nigra and
subthalamus are also
involved in basal nuclei
loops.

Red Reticular Reflex

Nucleus Formation Movement
Pons Medulla
Vestibular
Nuclei
P.T. Ex.-P.T.

1 2 `2 3 4 Tectum
5

local interneurons Spinal

&
Brainstem
Reflexes
alpha and gamma
(final common pathway)
P.T. = Pyramidal Tracts
neurons in motor nuclei
Ex-P.T. = Extra-pyramidal Tracts 58
 ADDENDUM
Movement and Posture Overview

Comments:
• Posture and movement result from excited alpha and gamma motor neurons (a motor
unit is one neuron plus all of the muscle fibers it innervates).

• Interneurons "hardwire" motor neurons so that logical movement patterns are pro-
duced (e.g., synergists are excited & antagonists are inhibited) Thus, most descending path-
way axons synapse on interneurons. However, a minority of descending axons synapse di-
rectly on motor neurons (e.g., vestibulospinal axons; a minority of pyramidal tract axons
synapse directly on motor neurons that innervate digits in primates and raccoons).

• Both voluntary and reflex pathways compete for control of the same interneurons and
motor neurons. Thus voluntary neurons must suppress reflex neurons, and vice versa, to gain
control of motor units.

• Neurons initiate a voluntary movement by exciting a particular pattern of motor units

at a certain intensity
— while the movement is underway, feedback from proprioceptors influences subse-
quent neuronal activity in motor centers to effect the desired movement;
— the cerebellum influences neuronal activity in the initiating motor centers (the
cerebellum continuously modulates neuronal activity, based on information about motor
commands and proprioceptive feedback about position and acceleration).
59
Lecture 9

Cerebral Hemisphere and Cortex

Cerebral Hemisphere
Right & left cerebral hemispheres are derived from the embryonic telencephalon. They are
composed of gray and white matter.

Gray Matter:
Cerebral Cortex — layer of gray matter at the surface of the cerebral hemisphere.
Three phylogenetic categories of cerebral cortex are:
• archicortex — (hippocampus) oldest, composed of two layers
• paleocortex — (piriform lobe) old, three layers, olfaction related
• neocortex — new, six layers, detailed perception, learning, intelligence

Basal Nuclei — gray matter nuclei located deep within the white matter of the cerebral
hemisphere. Basal nuclei include: caudate nucleus, putamen, pallidum, claustrum.

White Matter:
Myelinated axons which connect cerebral cortex with other brain regions. Three cat-
egories of white matter fibers are recognized:

Projection Fibers — fibers that leave the cerebral white matter. Projection fibers form
the internal capsule. Two categories of projection fibers are:
1] corticofugal: terminate in the basal nuclei, brainstem, or spinal cord;
2] corticopedal: typically originate in thalamus & terminate in cerebral cortex.

Commissural Fibers—fibers that connect cortices of right and left cerebral

hemispheres. The largest bundle forms the corpus callosum.

Association Fibers—fibers that connect regions of the cerebral cortex within one
hemisphere. Two categories are recognized:
short association fibers connect adjacent gyri;
long association fibers connect distant gyri (different lobes);
Note: The ventromedial portion of each cerebral hemisphere is designated rhinencephalon
because it is association with olfaction, the most primitive sensory modality.

Cerebral Cortical (Neocortex)

Neocortex, the phylogenetically most recent cortex, is only found in mammals. It is organized
horizontally into six layers and varies in thickness among different regions of the hemisphere.
Neocortex is involved in detailed sensory perception, in performing rapid sequences of fine-
movements, and in learning and intelligent behavior. It is most abundant in the human brain. It forms
about 85% of the dog cerebral cortex (the remaining 15% being archicortex and paleocortex).

60
 Two neuron types predominate in the neocortex:
pyramidal cell — conical cell body (>30 µm in diameter) with apical and basal den-
drites and an axon that leaves the base of the cell to enter white matter. Pyramidal cells vary in size.
They are the output cells of the cerebral cortex.
granule cell — small, round cell body (<10 µm in diameter). Granule cells serve as
interneurons, receiving input from cortical afferent fibers and synapsing on output neurons (pyrami-
dal cells) of the cortex.

Two types of afferent projection fibers from the thalamus enter the neocortex:
specific afferents — modality specific input; terminate in inner granule cell layer
non-specific afferents — background excitation; terminate in molecular layer.

Fig. 1. Six layers of cerebral cortex as seen with three stains used to show different histologic fea-
tures (axons; cell bodies; & whole neurons). The six layers are numbered at the left and named at the
right. P = pyramidal cell; S = granule (stellate) cell.
61
Horizontal Layers of Cerebral Cortical
The cerebral cortex is organized into six horizontal layers (although layer boundaries are not
very obvious in routine sections). The individual layers have different roles and vary in relative thick-
ness among cortical regions (e.g., a sensory region has a thick internal granule layer; a motor area has
a thick internal pyramidal cell layer).
From superficial to deep, the six layers are:
1] Molecular layer — fiber layer; apical dendrites & non-specific afferents;
2] Outer granule cell layer — interneurons for non-specific afferent input;
3] Outer pyramidal cell layer — small and medium cells; short association output
4] Inner granule layer — interneurons for specific afferent input
5] Inner pyramidal layer — large cells; projection & long association output
6] Multiform layer — variably shaped cells; projection & long association output

Cell Column (Vertical) Organization of Cerebral Cortical

The entire cerebral cortex is organized into functional units, each unit being a column (about 0.4
mm diameter) extending the entire thickness of the cortex (including all six layers). Each vertical column is a
functional unit because all cells within an individual column are activated by the same particular
feature of a stimulus. The vertical organization is the result of neuronal connections within a cortical
column:
— non-specific input to the column terminates in the molecular layer on distal dendrites of
pyramidal cells, to provide background excitation to the column;
— specific thalamic input terminates in the internal granule layer, exciting interneurons which
excite other neurons of the column;
— small pyramidal cells send their axons into the white matter to excite nearby cell columns;
— large pyramidal cells (and multiform cells) send their axons into the white matter to excite
distant sites via long association fibers, commissural fibers, and corticofugal projection fibers.

Fig. 2. Vertical cells

columns constitute the
functional units of cerebral
cortex. Usually the func-
tional columns are not
anatomically distinct, but
in the case of the massive
sensory input from rat
vibrissae, the cell columns
per vibrissae are morpho-
logically evident and give
the impression of a “bar-
rel”.

62
Functional areas (regions) of cerebral neocortex:
Motor area: somatotopically organized around the cruciate sulcus. The motor area drives
voluntary movement and it is the primary source of pyramidal tract fibers to cranial nerve nuclei and
spinal cord (corticospinal tracts).

Somatotopic organization = organization based on regional organization of the

body (e.g., neck is near the head; hindlimb is near the tail; etc.). The organization
can be represented by an animunculus, which appears distorted because amount of
cortex is proportional to density of innervation, not area of body surface.

Primary sensory areas: receive specific afferents of a given modality from the thalamus or
geniculate bodies:
• somesthetic (somatosensory) area — receives specific tactile input as well as information
related to pain, temperature and pressure sensation. The area is
somatotopically organized around the coronal sulcus.
• visual area — receives visual input. The area is retinotopically organized in the occipital
lobe around the marginal sulcus.
• auditory area — receives auditory input. The area is cochleotopically organized around the
apex of the pseudosylvian fissure.
• vestibular area — receives vestibular apparatus input. It is rostral to the auditory area.

Note: Taste is represented in the somesthetic area near the tongue region.
Olfaction is conscious detected at the piriform lobe (paleocortex).

Association areas:
These are cortical areas that receive their specific input from other cortical areas, and
so they are not involved directly with processing sensory and motor information. Rather these areas
are involved integrating and interpreting information derived from primary sensory areas.
There are different hierarchies of association areas: the lowest association areas
(adjacent to primary sensory areas) extract significance from components of a stimulus, the highest areas
are involved with thought, planning, memory, speech, creativity, etc. Association areas comprise 20% of the
canine brain and 85% of the human brain.

Note: In humans, language processing (written, vocal, signing) occurs in one cerebral
hemisphere (left hemisphere in 95% of right handed and 70% of left handed persons) and visual-
spatial processing (shapes, symbols, patterns, configuration analysis) is dominant in the other
hemisphere. Handedness is also a representation of hemispheric dominance.

Methods of Determining Cortical Function:

Destructive Lesions — information obtained by producing experimental lesions and by

observing patients whose lesions can be confirmed at necropsy. Findings include:

Somesthetic area — loss of the fine aspects of discrimination (e.g., cats loose the
ability to discriminate various degrees of texture roughness)

63
 Auditory Area — bilateral lesions cause difficulty in localizing sounds and the
meaning (temporal & pitch pattern) of sound is lost.

Electrical Stimulation — stimulate with electrodes and observe the resulting response.

Motor area — stimulation of the area surrounding the cruciate sulcus causes
contraction of contralateral muscles in a somatotopic pattern.

Electrical Recording — following a stimulus the corresponding primary sensory areas

become excited first. Next sensory information is relayed to association areas of cortex.

Primary auditory area — high frequency tones; activate neurons in the caudal sylvian
gyrus; low frequency tones activate neurons in the rostral sylvian gyrus
(tonotopic organization).

Primary Visual Area—cell columns respond to edges, flashes, colors, and

intensities the elements that comprise an image.

Metabolic Mapping — mapping studies utilize a radiolabeled glucose analogue, 2-deoxyglucose,

which competes with glucose for neuronal uptake. During a particular brain function, neurons
which are active utilize more glucose and thus take up more of the 2-deoxyglucose. These
neurons become highly radioactive and can be localized with autoradiographic techniques.

Figure 3: Diagram of a right cerebral

hemisphere illustrating locations of
the primary motor area and various
primary sensory areas.

Figure 4: A schematic diagram

illustrating a left cerebral
hemisphere of a cat. Represen-
tation of the motor area and
somethetic are is shown by an
animunculus in each case. The
anumunculus displays the the
amount of cortical surface
devoted to each region of the
body. Notice that the hindlimbs
and tail extends onto the medial
surface of the hemisphere.

64
Lecture 11

Nociception II
1. The Spinocervicothalamic (Spinocervical) Pathway--this pathway appears to play an equally
important role in pain transmission in carnivores (it is less well developed in humans and in other
domestic animals).

A. Receptors: Free nerve endings

B. 1st order neurons: Dorsal Root Ganglion

C. 2nd order neurons: Marginal Nucleus or Nucleus Proprius

D. Axons of these 2nd order neurons ascend ipsilaterally to the upper cervical spinal cord to
synapse on 3rd order neurons located in the Lateral Cervical Nucleus. (see Fig 1 below)

E. Axons from 3rd order neurons in the lateral cervical nucleus cross the midline and ascend to
the contralateral thalamus where they terminate on 4th order neurons.

F. The axons of these 4th order neurons project to the somatosensory area of the cerebral
cortex.

Spinothalamic Pathway (pain & temperature)

Spinothalamic Tract
Dorsomarginal Nuc.
midline

Spinal Cord BRAIN

Pelvic limb neuron Thoracic limb neuron

Spinocervicothalamic Pathway (touch and pain)

Spinal Cord
Dorsal horn Spinocervicothalamic Tract BRAIN
midline Medial
lemniscus
to thalamus
C-1,2

Lateral Cervical Nuc.

Pelvic limb neuron Thoracic limb neuron

Fig. 1: Diagrams of the spinothalamic and spinocervical pathways.

71
Note: The major difference between the spinocervical pathway (4 neuron pathway) and the
spinothalamic pathway (3 neuron pathway) is the presence of an additional neuron (located in
the Lateral Cervical Nucleus of the cervical spinal cord) in the pathway.

III. Types of Pain:

A. Transient Pain—elicited by activation of nociceptive transducers in skin or other tissues of
the body in the absence of any tissue damage. It is evoked to protect animals or humans from
physical damage by the environment or by excessive stress of the body tissues.

B. Acute Pain (Prolonged, subchronic, e.g. surgical pain; inflammatory pain)—elicited by

substantial injury of body tissue and activation of nociceptive transducers at the site of local
tissue damage. The local injury alters the response characteristics of nociceptors, their
central connections and the autonomic nervous system in the region. This type of pain is
seen after trauma, surgical interventions and some diseases. Lasts a few days or weeks, but
“healing” typically occurs.

C. Persistent or Chronic Pain—(arthritis; neuropathies, back pain, etc.) are commonly

triggered by an injury or disease, but may be perpetuated by factors other than the cause of
the pain. Because chronic pain is unrelenting (lasting months or longer), it is likely that
stress, environmental, and affective factors may be superimposed on the original damaged
tissue and contribute to the intensity and persistence of the pain.

Note: The central (CNS) and peripheral (PNS) nervous systems are dynamic, not static, and are
modulated by tissue damage and injury. In the spinal cord, immune-like glial cells
(astrocytes & microglia) are activated in response to subcutaneous inflammation, nerve
trauma, and tumors. These glia are involved in the creation and maintenance of
pathological pain states, in part by releasing proinflammatory cytokines (TNF, IL-1,etc.).

THE ENDOGENOUS ANALGESIA (Pain Suppression) SYSTEM:

Since the pioneering studies of Magoun and colleagues, it was known that the brain stem can
exert a strong control over the spinal cord. Reynolds was the first to demonstrate in 1969 that potent
analgesia could be produced by electrical stimulation of the midbrain in freely moving animals. We
now know that narcotic drugs (e.g. morphine), acupuncture, certain types of hypnosis and electrical
stimulation in selected brain regions will activate this endogenous analgesia system resulting in a
profound reduction in pain sensation.

Components:

1. Midbrain Periaqueductal Gray (PAG)—the region surrounding the mesencephalic

aqueduct. It contains a high density of opiate receptors and has direct connections with the spinal
cord and the nucleus raphe magnus. Activation of this region by an opiate drug, acupuncture or direct
stimulation activates a descending pathway that excites neurons in the nucleus raphe magnus and
consequently inhibits spinothalamic and spinocervicothalamic neurons in the spinal cord.

72
 2. Nucleus Raphe Magnus—located in the midline of the rostral medulla. The neurons that
comprise this nucleus contain high levels of the indoleamine neurotransmitter, serotonin and they
send their axons to the spinal cord dorsal horn, where they synapse on projection neurons in the
marginal nucleus and nucleus proprius. Release of serotonin causes inhibition of pain transmission
neurons in these nuclei of the dorsal horn.

3. Nucleus Locus Coeruleus—located in the caudal pons near the floor of the fourth ventricle.
The neurons here contain the monoamine transmitter, norepinephrine and their axons also synapse
on neurons in the dorsal horn of the spinal cord and cause inhibition of pain transmission neurons.
These components are summarized on the following page.

The system is organized such that various stimuli or natural events, including stress, fear,
exercise and pain itself can activate the PAG which in turn activates the nucleus raphe magnus and
locus coeruleus. These nuclei in turn send descending axonal projections via the dorsolateral
funiculus and the ventrolateral funiculus, respectively, to inhibit spinal cord dorsal horn neurons.
When this system is active it leads to suppression of nociception or pain. It is interesting to note that
female animals have a separate descending system from the PAG that is sensitive to estrogen. This
unique descending inhibitory system appears to be active when blood levels of estrogen are high,
such as during birth.

Endogenous Pain Activation System:

There also appears to be an endogenous pain activation system that actually enhances pain. This
pain enhancement system appears to help maintain chronic pain status. We are just beginning to
learn about this system which also seems to be centered in the brainstem. The periaqueductal gray
and the raphe magnus have collections of two physiologically
different types of neurons that appear to be related, on the one
hand, to pain enhancement and, on the other hand, to pain
suppression.

locus
midbrain periaqueductal coeruleus
medulla oblongata
gray pons

nucleus
raphe
magnus

+ locus spinal cord

- dorsal horn
coeruleus
periaqueductal
gray
-
nucleus
+ raphe -
magnus 73
Pain Relief in Animals:

1. Drugs: Apirin, Rimadyl (carprofen, a non-steroidal anti-inflammatory drug), butorphanol

2. Acupuncture-The effects of acupuncture on the central and peripheral nervous system

include activation of the body’s endogenous pain modulatory systems, causing a release
of nor-epinephrine, opioid substances and other neurotransmitters, thereby altering
nociceptive processing and perception. (for additional information, see the review by
Mittleman and Gaynor, JAVMA 217:1201, 2000).

74
 Size Range of Peripheral Nerve Fibers

Efferent Fibers Fiber Diameter Afferent Fibers

20 µm
—
Extrafusal muscle fibers —
annulospiral spindle endings Ia
—large motor units —
16 µm
ALPHA —
—
tendon organs
Ib
—
A Extrafusal muscle fibers
—small motor units
12 µm
—
— secondary spindle endings
BETA
— encapsulated receptors in II
— joints and skin

GAMMA Intrafusal muscle fibers —

6 µm
—
DELTA — hair follicle receptors
3 µm free ending mechanoreceptors
— pricking pain receptors
III
B GVE Preganglionic —
1 µm
non-myelinated slow pain nociceptors
C GVE Postganglionic
0.2 µm thermoreceptors IV
NOTE: Conduction velocity (m/sec) = fiber diameter (µm) X 6 (approximately).
Thus, a 20µm fiber conducts at approximately 120m/s = 270 mph.

Schematic illustration of free nerve endings.

75
Lecture 10

Nociception I
Overview of Pain
I. Terminology:
A. Pain—an unpleasant sensory and emotional experience associated with actual or potential tissue
damage. It is a protective mechanism for the body and causes a human or animal to react to
remove the pain stimulus. It is a complex sensory experience with many subjective compo-
nents: 1) discriminative; 2) learning and memory—associate pain with certain events; 3) un-
pleasantness, displeasure and 4) suffering, escape.

B. Noxious—a stimulus that damages or threatens damage to tissue, it can be mechanical, thermal
or chemical.

C. Nociceptor—a primary afferent neuron that is preferentially sensitive to a noxious stimulus.

D. Nociception—the detection of tissue damage by specialized transducers (nociceptors) attached

to “A delta” and “C” peripheral nerve fibers. The term “Nociception” is often used interchangably
with the term “Pain”, but technically refers to the transmission of nociceptive information to the
brain without reference to the production of emotional or other types of response to the noxious
stimulus.

E. Algesic—pain producing vs. Analgesic—pain preventing

F. Hyperalgesia—increased pain sensation elicited by a noxious stimulus

G. Allodynia—a pathological condition in which pain is produced by a stimulus that is normally

innocuous (sunburn).

65
II. How to Recognize Pain in Animals:
1) Altered Behavioral Responses—increased aggressiveness, avoidance behavior, reluctance
to be touched, decreased appetite, lethargy.
2) Altered Autonomic Function—increased heart rate, increased respiratory rate (hyperventi-
lation), increased sweating, salivation.
3) Lameness
4) Vocalization— crying/ yelping

III. Pain Transmission and Pain Pathways:

A. Peripheral Transmission: Pain or nociception is initiated when the peripheral terminals

(receptors) of a subgroup of sensory neurons (nociceptors) are activated by noxious chemi-
cal, mechanical or thermal stimuli.
1. Receptors — free nerve endings (unmyelinated terminals which contain synaptic
vesicles). Damage to tissue causes the release of a number of mediators that activate
nociceptor free nerve endings. These mediators include ATP from damaged cells and
bradykinin from blood (Fig. 2 ). In response to activation these terminals may actually
release their transmitters (substance P, CGRP and other peptides) into the extracellular
fluid in the area that they are located, this amplifies the pain sensation (Substance P for
example causes neurogenic inflammation by inducing mast cell degranulation).

Fig. 2: Influence of inflammatory mediators upon the activity of a “c-fiber” nociceptor

following injury. Following injury a variety of mediators are secreted by blood
vessels and other cells in the region which activate pain terminals by increasing
conductance of sodium (gNA) or calcium (gCa2+) channels or by activating second
messenger systems (adenylate cyclase, AC, etc.). Pain terminals then conduct an
electrical signal to the spinal cord.

66
2. Peripheral nociceptors have their cell body
or soma in a dorsal root or cranial nerve
ganglia. The cell body gives rise to: 1) a
peripheral process or primary afferent
axon that innervates skin, muscle, viscera,
etc. as a free nerve ending and 2) a central
process that terminates in the spinal cord Fig. 3: Diagram of a nociceptor show-
dorsal horn or in the brain stem. ing the cell body and processes.

Pain Sensitivity: Pain receptors become sensitized after tissue damage. When tissue
is damaged or a noxious stimulus is repeated nociceptors exhibit sensitization in
that there can be a reduction in the threshold for activation, an increase in response
to a given stimulus, or the appearance of spontaneous activity. This sensitization
results from the actions of second messenger systems activated by the release of
inflammatory mediators (bradykinin, histamine, prostaglandins, serotonin) at the
site of injury. This causes some of the features of hyperalgesia produced by tissue
damage or by pathological processes.

3. Noxious information is transmitted from nociceptive receptors by two types of axons:

(1) A-delta fibers—lightly myelinated, conduct at velocities of 2-30 M/sec (1st pain)
(2) C-fibers—unmyelinated, conduct at velocities of less than 2 M/sec (2nd pain).

NOTE: Aδ and C fibers can be classified into various types based on their functional properties. For
example C fibers can be divided into: C-mechanical/heat nociceptors; C Polymodal
Nociceptors (sensitive to heat, mechanical & chemicals) and Cold Nociceptors.

4. Primary Reponse Characteristics (code intensity of stimulus):

Mechanical Stimulation:
action potentials:

innocuous innocuous light hard

brushing pressure pinch pinch

Thermal Stimulation:
action potentials:

50° C
45° C
40° C
30° C

Figure 4: Response characteristics of C polymodal (mechanoheat) nociceptors.

67
68
 B. Central Transmission: Pain is transmitted from Primary Afferent Axons (axons from cell
bodies in a spinal ganglion) —> the spinal cord dorsal horn (marginal nucleus or nucleus
proprius) —> thalamus —> cerebral cortex

Pain sensation is conveyed from the spinal cord by several central nervous system
pathways, the two most important in animals are: (1) the Spinothalamic Path-
way and (2) the Spinocervicothalamic Pathway.

1. The Spinothalamic Pathway—this pathway is classically considered to be the major pain

relay system in mammals. Although this pathway clearly plays an important role in carnivores, the
spinocervicothalamic pathway (discussed in pain lecture 2) plays an equally important role in pain
transmission in dogs and cats. The organization of the spinothalamic pathway can be summarized
as follows:

(A). 1st Order Neuron—Cell body located in a spinal (dorsal root) ganglion; its peripheral
process is associated with the receptor, while its central process enters the gray matter of the
cord to synapse in the marginal nucleus (lamina I), substantia gelatinosa (lamina II) and
deeper laminae [Fig. 5].

Note: The transmitters utilized by these first order neurons are glutamate and aspartate. In addition,
several peptides (Somatostatin, Substance P) are present which may modulate the effects of excita-
tory amino acid transmitters.

Fig. 5: Diagram illustrating the termination sites of nociceptive fibers in the

marginal nucleus and nucleus proprius.

(B). 2nd Order Neuron—cell body located in the marginal nucleus and the nucleus pro-
prius. The axons of second order neurons cross the midline (decussate) and join other axons which
also carry pain sensation. These axons collectively form a tract in the ventral part of the lateral
funiculus called the Spinothalamic Tract (Fig. 6 ). The axons of 2nd order neurons in this pain
pathway travel through the brain stem to terminate in the thalamus.

(C). The axons of 2nd order neurons synapse on 3rd order neurons in the thalamus. The thalamus
is the crucial relay for the reception and processing of nociceptive information en route to the cortex.
Axons terminating in the lateral thalamus mediate discriminative aspects of pain. Axons terminating
in the medial thalamus mediate the motivational-affective aspects of pain (eg. relationship between
emotion [mood] and pain; attention to and memory of pain).
69
 (D). These 3rd order neurons in the thalamus in turn send their axons to the cerebral cortex.
Note: Neurons in the lateral thalamus (for discrimination) project to the somatosensory cortex;
Neurons in the medial thalamus (for affective aspects of pain) project to other areas of cortex (pre-
frontal, insular and cingulate cortex).

Note: An animal becomes aware of painful stimuli at the level of the thalamus, the
cerebral cortex is required for localization of the pain to a specific body
region. It should also be noted that in addition to pain the spinothalamic pathway
conveys temperature sensation.

Fig. 6: Simplified diagrams illustrating the main features of the

spinocervicothalamic pathway and the spinothalamic pathway.

70
Lecture 12

Cerebellum
Objectives:
1) To learn the basic anatomical organization and functional roles of the cerebellum.
2) To understand the anatomical and chemical organization of the cerebellar cortex
(i.e., cell layers, cell types, and neurotransmitters).
3) To appreciate the clinical abnormalities that occur following cerebellar damage.

Location:
The term cerebellum literally means little brain. The cerebellum is located dorsal to the
brainstem. It is connected to the brainstem by three pairs of cerebellar peduncles.

Functions: — three major functional roles:

1. Coordination of Movement—the cerebellum controls the timing and pattern of

muscle activation during movement.

2. Maintenance of Equilibrium (in conjunction with the vestibular system).

3. Regulation of Muscle Tone—modulates spinal cord and brain stem mechanisms

involved in postural control.

Dysfunction:
Damage (lesions) to the cerebellum result in the following:

1. Ataxia—a disturbance that alters the direction and extent of voluntary movements; it
is characterized by abnormal gait & uncoordinated muscle movements.

2. Dysmetria—altered range of motion (misjudge distance)

3. Intention Tremor—oscillating motion, especially of the head, during movement.

Gross Anatomical Organization:

1. Internal Organization (similar to cerebral hemisphere):

Cerebellar Cortex — surface gray matter; divided by sulci into folia (small folds)

White Matter — internal

Cerebellar Nuclei — three pairs located deep in the white matter;

named from medial to lateral: Fastigial, Interpositus & Dentate

76
 2. Cerebellar Lobes:
A. Rostral Lobe = Spinocerebellum (paleocerebellum) — related to spinal cord,
associated with postural tone. Damage results in forelimb hyperextension and hindlimb hip flexion.

B. Caudal Lobe = cerebrocerebellum (neocerebellum) — Damage results in hypoto-

nia, hypermetria, and intention tremor.

C. Flocculonodular Lobe = vestibulocerebellum — associated with the vestibular

system; involved in control of eye movements and balance. Damage results in dysequilibrium,
wide-based gait, nystagmus.

3. Longitudinal Zones:
A. Vermis — the most medial portion of the cerebellum, associated with the fastigial
nucleus — concerned with regulation of muscle tone for posture and locomotion.

B. Paravermis — intermediate part of the cerebellum, associated with the underlying

interpositus nucleus — participates in the control of an evolving movement by utilizing propriocep-
tive sensory information generated by the movement itself to correct errors in the movement.

C. Hemispheres — the largest and most lateral part of the cerebellum, associated
with the dentate nucleus — influences the output of the motor cortex and thus permits fine, delicate
adjustments in muscle tone that are important for skilled movements.

Cerebellar Peduncles (named by position):

1. Caudal Cerebellar Peduncle — connects the cerebellum with the medulla, contains both
afferent and efferent fibers.

2. Middle Cerebellar Peduncle — connects cerebellum with the pons, contains entirely
afferent fibers (axons) arising in from the pontine nuclei and terminating in the cerebellum.
77
 3. Rostral Cerebellar Peduncle—connects the cerebellum with the midbrain; it is predomi-
nantly an efferent fiber bundle (carrying axons out of the cerebellum to other brain regions).

Cerebellar Cortex: the surface gray matter of the cerebellum, consisting of three layers:
1. Molecular Layer — the most superficial layer, consisting of axons of granule cells (termed
parallel fibers) and dendritic processes of Purkinje cells.

2. Purkinje Cell Layer — the middle layer of the cortex consisting of a single layer of large
neuronal cell bodies, termed Purkinje cells.

3. Granule Cell Layer — the deepest layer of cerebellar cortex found adjacent to the white
matter; consists predominantly of small neurons called granule cells.

Cell types & Afferent Fibers of the Cerebellar cortex:

1.Purkinje Cells — the only output neurons from the cortex; utilize GABA as an inhibitory
neurotransmitter; inhibit neurons in the deep cerebellar nuclei
2. Granule Cells — intrinsic cells of the cerebellar cortex, utilize glutamate as an excitatory
transmitter; excite Purkinje cells via parallel fibers
3. Basket Cells — inhibitory interneurons; utilize GABA to inhibit Purkinje cells
4. Climbing Fibers — arise from the olivary nucleus and terminate on Purkinje cells;
thought to utilize glutamate and aspartate as excitatory transmitters
5. Mossy Fibers — fibers that enter the cerebellum from all other sources except the olivary
nucleus (i.e., spinal cord, pontine nuclei, etc.); synapse on granule cells & excite them.

78
Major Cerebellar Inputs (axons entering the cerebellum):

1. Climbing Fiber Inputs = Olivocerebellar Fibers

— arise exclusively from the olivary nucleus of the caudal medulla; have a powerful
excitatory effect on the Purkinje cells upon which they synapse.

2. Mossy Fiber Inputs:

A. Vestibulocerebellar Fibers — arise directly from the vestibular nerve and vestibular
nuclei; project primarily to the flocculonodular lobe and fastigial nucleus
[Helps coordinate head and eye movement].

B. Spinocerebellar Fibers — arise from the spinal cord (travel to cerebellum via dorsal
spinocerebellar and ventral spinocerebellar tracts); terminate predominately in the rostral lobe.
[Makes cerebellum aware of ongoing movements via proprioceptive input
from muscle spindles and joint receptors].

C. Cerebropontocerebellar Fibers — arise from pyramidal cells in the cerebral cortex,

synapse in the pontine nuclei which then send their axons to the contralateral cerebellar cortex via
pontocerebellar fibers (which form the middle cerebellar peduncle).
[Alerts the cerebellum about anticipated movements].

Major Cerebellar Outputs (arise from neurons in deep cerebellar nuclei):

1. Fastigial Nucleus Projections: (via caudal peduncle)

— go to vestibular nuclei and reticular formation; via vestibulospinal and
reticulospinal tracts, the projections ultimately influence primarily extensor muscles related to main-
taining posture and balance.

2. Interpositus Nucleus Projections: (via rostral peduncle)

— go to red nucleus to influence rubrospinal tract activity; the projections make correc-
tions related to gross movements of the animal.

3. Dentate Nucleus Projections: (via rostral peduncle)

— go to thalamus to influence output from the motor cortex; the projections make
delicate adjustments related to fine, skilled movements.

Clinical Abnormalities:

Lesions of the cerebellum (i.e., damage to cerebellar input, cerebellar output, or cerebellar
cortex) result in symptoms that occur because the cerebellum’s normal function is interrupted. Thus
ataxia, dysmetria, and intention tremor are the result of interference with the cerebellums normal role
in the coordination of movement and in the maintanence of equilibrium and appropriate muscle tone.

79
 Cerebellar disorders usually result from:
1. Tumors
2. Viral Infections (encephalitis) -- which may occur in utero
3. Heavy metal poisoning
4. Genetic disorders

1. Small lesions may produce no signs or only transient symptoms. The cerebellum seems to
have a relatively large margin of physiologic safety built into the system. Small deficits can often be
compensated for by other parts of the brain.

2. Lesions of the cerebellar hemispheres result in loss of muscular coordination and jerky
puppet-like movements of the limbs on the ipsilateral side (same side as the lesion).

3. Lesions of the vermis result in truncal tremor and gait ataxia (a splayed stance and swaying
of the body while walking).

80
Lecture 13

Diencephalon and Hypothalamus

Objectives:
1) To become familiar with the four major divisions of the diencephalon
2) To understand the major anatomical divisions and functions of the hypothalamus.
3) To appreciate the relationship of the hypothalamus to the pituitary gland

Four Subdivisions of the Diencephalon:

1. Epithalamus — (“epi” means upon) the most dorsal part of the diencephalon; it forms a
caplike covering over the thalamus.
a. The smallest and oldest part of the diencephalon
b. Composed of: pineal body, habenular nuclei and the caudal commissure (see fig 1)
c. Function: It is functionally and anatomically linked to the limbic system. It has been
implicated in a number of autonomic (ie. respiratory, cardio-vascular),
endocrine (thyroid function) and reproductive (mating behavior) functions

2. Subthalamus — (“sub” = below), located ventral to the thalamus and lateral to the
hypothalamus (only present in mammals).
a. Plays a role in the generation of rhythmic movements
b. Lesions in primates lead to hemiballism (a violent form of hyperkinesia)

3. Thalamus — largest component of the diencephalon

a. comprised of a large number of nuclei; the only two we ask you to know are the
lateral geniculate (vision) and the medial geniculate (hearing).
b. serves as the great sensory receiving area (receives sensory input from all sensory
pathways except olfaction) and relays sensory information to the cerebral cortex.

thalamus habenula
pineal gland

fornix
caudal
commissure
rostral
commissure

lamina midbrain
terminalis hypo-
thalamus mamillary body

optic chiasm
tuber cinereum neurohypophysis
adenohypophysis
Fig. 1. Schematic diagram illustrating the components of the diencephalon.
81
 4. Hypothalamus — (“hypo” = below), the most ventral part of the diencephalon; it is the most
significant component of the diencephalon from a clinical standpoint because lesions
result in abnormalities in endocrine, limbic and/or autonomic function

Hypothalamus:

1. Functions — its most important job is to maintain homeostasis; it does so by regulating

three interrelated functions:
a. Endocrine Secretion — controls hormone release by the pituitary gland.
b.Autonomic Function — integrates autonomic functions via direct projections
to preganglionic autonomic neurons located in the brain-stem and spinal cord.
c. Emotions and Drives — it has numerous interconnections with the limbic system

2. Subdivisions and Nuclei — the hypothalamus is small in size and presents no large
scale anatomical variations in different vertebrate species. It has three basic subdivisions
each of which contains various nuclei.

a. Supraoptic region — lies above the optic chiasm and contains three important nuclei:
1)Supraoptic Nucleus — contains neurons that produce antidiuretic hormone
(ADH or vasopressin); their axons project to the posterior pituitary
gland (neurohypophysis) where ADH is released and enters the blood.
2) Paraventricular Nucleus — contains neurons that produce predominately
oxytocin
3) Suprachiasmatic Nucleus — appears to be the hypothalamic nucleus
critically involved in controlling circadian rhythms (endogenous
biological rhythms that have a period of about 24 hours). The nucleus
synchronizes rhythms to light and dark. Other circadian rhythms:
sleep-wakefulness; body temperature.

b. Tuberal Region

c. Mamillary Region

3. Afferent Inputs to the Hypothalamus:

a. Brain Stem via the Medial Forebrain bundle

b. Limbic System via the fornix
c. Retina via direct branches of the optic nerve and tract
d. Blood (hypothalamic cells are sensitive to hormone concentrations,
glucose levels, etc.)

4. Major Efferent Projections From the Hypothalamus:

a. To the brain stem and spinal cord (via the dorsal longitudinal fasciculus)
b. To the thalamus (mammallothalamic tract)
c. To the limbic system
d. To the pituitary gland

82
Figure 2: Regions of the hypothalamus and pituitary gland in midsagittal view. Note the tuber
cinereum forms the floor of the hypothalamus between the optic chiasm & mammillary bodies. The
hypothalamus is divided in a rostrocaudal direction into 3 subdivisions: supraoptic, tuberal and
mammillary, respectively.

5. Relationship to Pituitary Gland:

[The pituitary gland lies beneath the brain
and is formed by 2 distinct parts: a neural
part, the neurohypophysis, and a glandular
component derived from oral epithelium,
called the adenohypophysis.]

The hypothalamus controls the endocrine

system via two different routes:
a. Directly by secretion of neuroendo-
crine products into the general circulation via
the vasculature of the posterior pituitary
gland (ADH and oxytocin).

b. Indirectly by secretion of releasing

factors into the local hypophyseal portal
venous plexus (which carries these releasing
factors from the base of the hypothalamus
[an area know as the eminence] to the ante-
rior pituitary). The hypothalamus thus con-
trols anterior pituitary hormone synthesis via
these releasing factors.

Fig. 3. Projections from the hypothalamus to

the pituitary gland. The hypothalamus is
connected directly via the axons of the su-
praoptic and paraventricular nuclei and indi-
rectly via the hypophyseal portal system.
83
Hypothalamic Function:

1. Direct effects on the Endocrine system;

Secretion of oxytocin and vasopressin into the circulation.

A. Oxytocin—(Greek for “rapid birth”)- Produced by: neurons in the paraventricular

nuclei of the hypothalamus. Functions: acts on uterine smooth muscle to stimulate myometrial con-
tractions and accelerates parturition (thus oxytocin or synthetic derivatives of oxytocin can be used to
induce parturition, eg. in the mare). Activates milk letdown reflex in response to suckling (induces
contraction of myoepithelial cells in mammary gland).

B. Vasopressin (ADH): Produced by: neurons in the supraoptic nucleus. Function: to

increase reabsorption of water in the kidneys (via collecting ducts and convoluted tubules). Thus it de-
creases urine production and conserves body water. Capillary density of the supraoptic nucleus is
higher than any other part of the brain and increases in blood osmolarity stimulate release of ADH.

Disease State: Diabetes Insipidus — loss of control of water excretion due to a

failure of production, transport or release of ADH into the blood stream.
Commonly associated with tumors of the adenohypophysis.

2. Indirect effects on the endocrine system: Production and release of hypothalamic releas-
ing factors which either stimulate or inhibit the release of hormones from the anterior pituitary gland.

Disease: Hyperadrenocorticoidism often accompanies tumors of the

adenohypophysis which produce excess adrenocorticotropic hormone.
Symptoms: Extremely hungry; hair loss from the body; enlarged liver; lameness with
skeletal muscle atrophy.

3. Control of the Autonomic Nervous System

Stimulate rostral hypothalamus — parasympathetic responses (e.g., slowed heart rate).

Stimulate caudal hypothalamus — sympathetic responses (e.g., increased heart rate,

vasoconstriction, etc.)

Disease: alterations in cardiovascular function have been observed in cattle with

abscesses of the hypothalamus (slowing of heart rate).

4. Temperature regulation:
a. Rostral hypothalamus — heat loss center: warm blood, antipyretic substances or
impulses from heat receptors cause panting, vasodilation and sweating which serve to reduce body
temperature.

b. Caudal hypothalamus — heat conservation center: cool blood, pyrogenic sub-

stances or input from cold receptors causes shivering and vasoconstriction which serve to increase
body temperature.

84
 Disease: damage to the rostral hypothalamus can cause hyperthermia (fever) while dam-
age or lesions to the caudal hypothalamus can cause hypothermia (decreased
body temperature); e.g., cattle with abscesses of the pituitary gland that effect
the hypothalamus are often hypothermic.

5. Regulation of Food and Water intake:

Disease: Lesions of the hypothalamus often cause abnormal eating and drinking
behavior (see Fig. 4, below).

6. Behavior: together with the limbic system the hypothalamus participates in behavioral cir-
cuits responsible for controlling an animals behavior.

Diseases:
A. Lesions of the hypothalamus in cats can cause rage reactions

B. Cattle with pituitary abscesses that effect the hypothalamus are often
depressed and hold head and neck extended as if “star gazing”.

Fig. 4. The effect of

discrete bilateral le-
sions in specific hypo-
thalamic areas on ap-
petite in the cat. Le-
sions of the ventrolat-
eral nuclei produce
hyperphagia, while le-
sions of the extreme
lateral hypothalamus
produce loss of appe-
tite (Anorexia).

85
Lecture 14

Olfaction and The Limbic System

Objectives:
1. To understand the anatomical organization of the olfactory system
2. To understand the concept of the “limbic” system
3. To be able to identify the major components of the limbic system and
associate these components with limbic system functions

The Olfactory System:

1. Modality — Olfaction (SVA)

2. Receptors — bipolar cells located in the olfactory epithelium within the upper nasal cavity.

3. First Order Neurons = receptor cells = the bipolar olfactory neurons located in the olfac-
tory epithelium. The nonmyelinated axons of these neurons gather into bundles that collectively form
the olfactory nerve. Olfactory nerve bundles penetrate the cribiform plate of the ethmoid bone to enter
the olfactory bulb.

4. Second Order Neurons = mitral cells in the olfactory bulb. The axons of these cells form
the olfactory tracts (striae).
[Histologically, the olfactory bulb features several layers, including from superficial to deep, a
glomerular layer, where olfactory nerve fibers synapse on the dendrites of mitral cells; a mitral cell
layer and a granule cell layer.]

5. The olfactory tract terminates by bifurcating into a medial and lateral olfactory stria which
project, respectively, to the septal area (olfactovisceral reflexes) and piriform cortex (conscious
awareness of olfaction).

Fig. 1. Cellular
components of the
olfactory mucosa
and olfactory
bulb.

86
Fig. 2. The olfactory epithelium. A) Schematic illustration of the olfactory epithelium, showing the major cell
types. The inset shows the location of putative 7 transmembrane odorant receptors (7TMr) on cilia of olfactory
receptor neurons. B) Hypothesized olfactory receptor-transduction mechanisms. Odor molecules bind to spe-
cific 7TMr proteins located in the cilia. These 7TMrs are thought to be coupled to G proteins that activate ei-
ther adenyl cyclase (AC) to generate cAMP or phospholipase C (PLC) to generate phosphitidal inositol (IP3).
These second messengers open channels that admit calcium or sodium into the cilium. Entrance of these ions
lead to membrane depolarization and the generation of action potentials that are conducted along olfactory
nerve fibers to the olfactory bulb.

87
Historical Perspective:
The term limbic is derived from the latin word “limbus” which means “border”. Limbic refers to fact that
the cortical structures which comprise the system form a border around the brainstem. James Papez suggested in 1937 that
the limbic structures which surrounded the brainstem were involved in emotions. This hypothesis was subsequently found
to be correct and these structures together with certain components of the hypothalamus, thalamus and epithalamus were
collectively called the.Limbic System

The Limbic System:

1. Functions:
In domestic animals the limbic system is concerned with
1) emotions of importance to survival (emotions associated with self preserva-
tion, such as escape, defense, feeding, etc.; and emotions associated with species preservation such as
territorial defense, courtship, mating, etc.) and
2) processes involved in learning and memory.

2. Criteria for being included in the limbic system:

A. Rich innervation by axons containing indoleamine (i.e., serotonin) and/or
catecholamine (i.e., dopamine or epinephrine) neurotransmitters
B. Low threshold for seizure activity
C. Direct or indirect connections to the hypothalamus

3. Components:
Hippocampus; Cingulate Gyrus; Amygdala; Septal Area; portions of the Thalamus;
Piriform lobe; and Mammillary Bodies of the Hypothalamus

Fig. 3. Illustrations of limbic structures on medial views of the brain. A. Cortical structures including
the cingulate gyrus and septum (septal area) are shown and the hippocampus has been dissected out to
display its anatomical location. B. Parts of the cortex and diencephalon have been removed to illus-
trate the fornix, mamillothalamic tract and other limbic structures.
88
Individual Limbic Structures and Possible Function:

In general the neocortex has a dampening effect on emotional behavior. This is illustrated
by sham rage— which occurs following removal of the cerebral cortex from a cat or dog. It is charac-
terized by: lashing of the tail, vigorous arching of the back, clawing and attempts to bite, and auto-
nomic responses. It is called sham rage because unlike genuine rage, the anger occurs spontaneously
or can be triggered by mild tactile or other nonnoxious stimuli.

Hippocampus — a three layered cortical structure (archicortex) which has long been thought to be an
important cortical region for associative learning and memory (particularly memory acquisition or
short term memory). Both amnesia patients and animals with hippocampal damage exhibit ‘time-de-
pendent impairments’ in behavioral tasks generally described as associative or relational in nature. It is
also important to note that this area of the brain has a very low seizure threshold.

Septum — a small but conspicuous cortical area that is involved in a variety of physiological and be-
havioral processes including emotions, relief of fear, docile behavior and stress, as well as, a role in
autonomic regulation (e.g., water/food intake, hibernation, etc.). Stimulation induces docile behavior
and can suppress many autonomic responses. Lesions result in rage and aggressive behavior and can
trigger many autonomic responses.

Amygdala — a highly differentiated region near the temporal pole of the mammalian cerebral
hemispere. It is a basal nucleus that is implicated in a bewildering variety of behavioral and regula-
tory functions. These include emotion and memory, social behaviors such as reproduction, fear and
aggression, and modulation of the autonomic and neuroendocrine systems. Many amgdala effects ap-
pear opposite to those of the septum. For instance, lesions result in docile behavior, while stimulation
produces rage and aggressive behavior.
[Note: Recent evidence indicates that the amygdala is neither a structural nor a functional co-
hesive unit, but rather it consists of different parts performing different functions. For instance, the
central nucleus of the amygdala projects to visceral areas of the brainstem and is a specialized auto-
nomic projecting motor region. In contrast the cortical amydala together with the nucleus of the lat-
eral olfactory tract form the caudal end of the piriform lobe and play a role in olfactory function.]

Hypothalamus — the functions of this area were discussed previously. It should be noted that be-
cause of its interconnections with other limbic structures, simulation of the hypothalamus produces
many of the behaviors seen with stimulation of other limbic sites. Thus stimulation reveals rage and
aggression sites as well as sites that produce cowering or docile behavior.

Thalamus — links the limbic system to the neocortex and provides a means by which sensory infor-
mation can gain access to the limbic system.

Also:
Rhinencephalon (nose-brain) — includes the piriform lobe and olfactory bulb. It is con-
cerned with olfaction and is a major component of the limbic system where it functions together with
other limbic structures in affective behavior (urges, behavioral drives).

89
Lecture 15

Cochlea and Auditory Pathways

Anatomical Considerations
External ear:
The external auditory meatus (canal) is formed by auricular and annular cartilages, plus a short contribution
from the temporal bone.

Middle ear:
Air-filled tympanic cavity (including a ventrally expanded bulla) that features:
— four openings (three sealed by membranes):
• auditory tube opening (not sealed) connects middle ear to the nasopharynx;
• tympanic membrane (ear drum) separates tympanic cavity from external auditory meatus;
• oval (vestibular) window separates the tympanic cavity from perilymph in the vestibule;
• round (cochlear) window separates tympanic cavity from perilymph in the scala tympani;
— three ossicles, malleus, incus, and stapes, transmit tympanic membrane movements
to the membrane of the oval window;
— two muscles reflexly dampen ossicle movement, to suppress forceful low frequencies:
• stapedius muscle, innervated by facial nerve, pulls the stapes away from oval window;
• tensor tympani muscle, innervated by trigeminal nerve, pulls malleus thus tensing the tympanic membrane.

Function of Middle Ear

To increases the efficiency of sound transmission. (Pressure oscillations in air (sound
waves) are very inefficiently converted to pressure waves in fluid, only 0.1% of the force is normally
transmitted.) Middle ear components convert large amplitude, low force input into low
amplitude, high force output. (The middle ear matches low impedance input to high
impedance output.)
Note: The tympanic membrane occupies a large area and undergoes a large excur-
sion, offering low resistance to being vibrated (by air pressure waves). The membrane
of the oval window has a small area and makes small excursions against high resistance
load (it must push against incompressible perilymph fluid and the round window. The
ossicles form a lever system that collects energy from the large tympanic membrane
and focuses it on the small oval window membrane (yielding a 60-fold force gain in the cat).

Inner ear:
The inner ear consists of the cochlea and vestibular apparatus. The cochlea is a component of
osseous labyrinth that contains perilymph and the cochlear duct. The cochlear duct is a component of
membranous labyrinth and contains endolymph.
The cochlea makes 3.25 turns in the dog (2.5 in man) around
a core of bone (called the modiolus) through which the cochlear nerve Cochlea
passes. The entire complex resembles a snail’s shell (whence the term bisected
cochlea is derived).
Within the cochlea, the cochlea duct (scala media)
separates two perilymph chambers: the scala vestibuli,
which contacts the oval window membrane, and the scala
tympani, which contacts the round window membrane.
Perilymph can flow from one scala to the other through an
opening (helicotrema) at the apex of the cochlea. The helicotrema is
non-functional with respect to the physiology of hearing, it merely cochlear nerve
precludes perilymph stagnation.
spiral ganglion

90
 The cochlear duct
(scala media) is triangular
in cross-section. A thin BONE Vestibular Cochlear
vestibular membrane Scala membrane duct
separates cochlear duct vestibuli
from scala vestibuli, Stria
vascularis
presenting an ionic barrier
between perilymph & Spiral
endolymph. Vestibular Basilar ligament
membrane can be ignored Spiral Osseous membrane
in regard to the mechanics ganglion spiral
of hearing. lamina Scala
tympani
An osseous spiral
lamina and basilar
membrane separate
cochlear duct from the scala tympani. Within the cochlear duct, a spiral organ sits atop the basilar
membrane along its entire length from the base to the apex of the cochlea.

The basilar membrane is critical in the physiology of hearing. It consists of radial fibers that
extend outward from the osseous spiral lamina. The fibers are shortest and stiffest at the base of the
cochlea and they are longest at the apex. (Conversely, the osseous spiral lamina, a spiral ledge that projects
outward from the modiolus, is longest at the base and shortest at the apex of the cochlea.)

BASE APEX
of cochlea of cochlea
The spiral organ (organ of Corti) features receptor cells (hair cells) arranged along one inner
row and three outer rows. Each hair cell has dozens of stereo-cilia on its free surface. Hair cells are
held in place by a reticular membrane (plate) anchored to the basilar membrane. Stereo-cilia project
above the reticular plate, making contact with a tectorial membrane. The tectorial membrane arises
from the limbus, a tissue mass set solidly on the osseous spiral lamina.

Afferent neurons of the cochlear nerve have Spiral tectorial

bipolar cell bodies located in a spiral ganglion, Organ membrane
within the modiolus. From the spiral ganglion, axons Limbus reticular
traverse the osseous spiral lamina. More than 90% axons membrane
of the axons synapse on inner hair cells. Less than
10% of the axons synapse on outer cells, which have mostly
a mechanical function adjusting the position of the tectorial inner outer
membrane via cellular elongation. sensory hair cells

Centrally, axons leave the spiral ganglion and pass through the center of the modiolus to form the
cochlear division of the vestibular-cochlear nerve. In the brain, axons synapse in dorsal and ventral
cochlear nuclei.

The cochlear nerve also contains inhibitory efferent axons (from dorsal nucleus of the trapezoid
body) that synapse on dendritic endings of afferent neurons and on outer hair cells. Via efferent
axons, the brain selectively “tunes” ear sensitivity (attention) to different ranges of sound pitch.
91
 BONE
Scala tympani
oval window helicotrema

Scala vestibuli
vestibular membrane
External Cochlear duct
incus
Auditory stapes
Meatus malleus basilar membrane
Scala tympani
tympanic
membrane round window
Middle
Ear
View from Scala tympani basilar membrane

osseous spiral lamina

Mechanics of Hearing
Hearing begins with pressure waves impacting the tympanic membrane, causing it to
vibrate. The vibration is transmitted from malleus to incus to stapes. The stapes rocks in & out,
causing the membrane of the oval window to produce pressure waves within perilymph of the scala
vestibuli. Pressure is transmitted without lost to endolymph in the cochlear duct (the vestibular
membrane offers no resistance to fluid pressure). The pressure wave displaces the basilar membrane,
transmitting pressure to the scala tympani and displacing the membrane of the round window.

As a pressure wave travels from the base to the apex of the cochlea, displacement to the
basilar membrane is greatest where the membrane is resonant to the frequency of the traveling wave.
High frequency traveling waves cause displacement at the base of the cochlear and low frequency
waves travel to the apex of the cochlea.

Movement of the basilar membrane imparts a rocking action, proportional to degree of

displacement, to the spiral organ which rests upon the membrane. Cilia, in contact with the stationary
tectorial membrane, are displaced relative to the moving hair cells. The tectorial membrane doesn’t
rock because it is attached to the limbus, which sits on bone (osseous spiral lamina).

Cilia displacement (in one direction) opens K+ channels leading to depolarization of hair
cells, release of glutamate neurotransmitter, depolarization of dendrites that synapse on the hair cells,
and increased frequency of action potentials in the cochlear nerve. Cilia displacement in the other
direction results in hyperpolarization and decreased frequency of action potentials.

Thus, cilia displacement modulates an on-going K+ current from the endolymph through the
hair cell to the perilymph. Hair cell excitability modulates actions potentials in the cochlear nerve.

Note: A common cause of deafness with advanced age is localized bone deposition that impedes the
rocking action of the stapes. This is called conduction deafness and it can be treated by a hearing aid
that amplifies sound or imparts vibration to perilymph through temporal bone contact.

92
 Perilymph Endolymph
&
Extracellular
K+
pump
_
_ +
_ +
_ +
_ +
_ +
K+ _
_
_
+
+ K+
_ +
_ +
_ +
_ +
_ +
_ +
+ _
_ +_ +_+ _+ +_ +_+ _+ +
_ +
_
+
_
+
_ K+
+
_
+
_ _ _ _ _ _ _ _
++++++++++
40mV

90mV

Pressure waves of air (20 to 20,000 Hz in man; up to 40,000 Hz in the dog &100,000 Hz in the bat)
can be interpreted as sound. Sound has subjective properties that correspond to parameters of physics:
pitch = wave frequency = Hz = Hertz = cycles/sec.,
volume = amplitude from the low point to the high point in a pressure wave, and
direction = location of the source of the sound waves.
(Sound also has “color”— higher frequencies impart overtones which enable one to distinguish
different instruments playing the same note at the same volume.)

Pitch — the brain deciphers pitch by determining which fibers of the cochlear
nerve (which hair cells of the spiral organ; what place along the basilar membrane)
are maximally active (for > 200 Hz). As the pitch (Hz) of a sound increases, the peak
amplitude of basilar membrane displacement regresses, from the apex (longest fibers)
toward the base (shortest fibers) of the cochlea. (Place principle: pitch is determined by
the place of maximal amplitude displacement along the basilar membrane.)
Volume — the brain interprets volume as a function of the number of axons
firing and the frequency of their action potentials. Increased volume (amplitude) will re-
sult in greater excursion of the basilar membrane, greater displacement of cilia, greater
depolarization of receptor cells, and higher frequencies of action potentials in more
cochlear nerve axons (whatever the pitch pattern of basilar membrane displacement).
Direction — at low frequencies, the brain uses the phase difference (time-lag)
between inputs to right and left ears to determine which ear is closer to the source of the
sound; at high frequencies, the head acts as a barrier resulting in an intensity difference
between the near and far ear. (Also, the pinna may modify sound coming from different
directions, and the animal can move its ears and head to assist in sound localization.)
93
 Auditory Pathway
Cochlear nerve fibers synapse in dorsal and ventral cochlear nuclei, typically each fiber
synapses in both nuclei. The cochlear nuclei contain second-order neurons. Thereafter, the auditory
pathway is bilateral and complex because of many synaptic possibilities.
We can say that more fibers decussate (in the trapezoid body) than remain ipsilateral, that
the pathway ascends in the lateral lemniscus and then in the brachium of the caudal colliculus,
and that the conscious sound pathway synapses in the medial geniculate body, from which neurons
send their axons through the internal capsule to cerebral cortex surrounding the sylvian sulcus
(primary auditory cortex).
Additional synaptic possibilities include: ventral nuclei of trapezoid body (gray matter among fibers of the
trapezoid body); dorsal nucleus of the trapezoid body; nuclei of the lateral lemniscus; and caudal colliculus.

Internal Capsule

commissure of
Auditory Medial caudal colliculus
Cortex Geniculate

Sylvian
Sulcus
Brachium of
Caudal Caudal Colliculus
Colliculus

White Matter
Gray Matter

Nuclei of
Lateral Lemniscus Lateral
Lemniscus
Dorsal Nucleus of
Trapezoid body commissure
of lateral Cochlear Nerve
lemniscus
Dorsal
and
Ventral Trapezoid Body
Cochlear Nuclei
Ventral Nuclei of Trapezoid Body

Comments about gray matter in the auditory pathway:

Cochlear nuclei (dorsal and ventral) — receive input from the ipsilateral cochlear nerve.
Second-order neurons, tonotopically organized within the nucleus, are the source of all central
auditory pathways. Like the cochlear nerve and the rest of the auditory pathways, second order
neurons exhibit continuous background firing that is increased/decreased by sound driven excursions
of the basilar membrane and spiral organ.

Lesions of cochlear nuclei (or cochlear nerve or a cochlea) produce unilateral deafness;
lesions central to the cochlear nuclei affect both ears (because central pathways are bilateral).
94
 Dorsal nucleus of trapezoid body — each nucleus receives input from right and left ears
(via cochlear nuclei). The nucleus functions in sound localization, i.e., detecting phase and intensity
differences between the two ears. (Different neurons respond to the different time lags between the
two ears. Other neurons respond to different intensity differences between the two ears.)
The nucleus sends output to cranial nerves V and VII for reflex contraction of tensor tympani
and stapedius muscles to dampen loud sound.
The nucleus is the source of efferent axons which selectively “tune” the spiral organ
for frequency discrimination (e.g., listening to the play of one instrument within an orchestra).
(Efferent innervation affects the length of outer hair cells which changes the position of the tectorial
membrane which adjusts the sensitivity of inner hair cells.)

Caudal colliculus — receives input via the lateral lemniscus. The colliculus contains neurons
that are sensitive to phase and intensity differences between the ears. Also, caudal colliculus neurons that project to the
medial geniculate are part of a conscious auditory pathway.
Via tectospinal/tectobulbar tracts, output from the caudal colliculus produces reflex turning of
the head, ears and eyes toward a sudden sound stimulus. (Collateral branches of auditory pathway axons go to
the reticular formation to alert the whole brain to a loud sound stimulation.)

Medial geniculate — receives input via the brachium of the caudal colliculus. Imprecise
sound consciousness takes place at the medial geniculate level.
Geniculate neurons project their axons through the internal capsule to the primary auditory
cortex. (Note: The geniculate body functions for sound like the thalamus functions for tactile sense.)

Primary Auditory Cortex — located around the sylvian sulcus, this cortex is necessary
for recognizing temporal patterns of sound and direction of pitch change, i.e., elements of melody,
speech, etc. The cortex has separate tonotopic maps for detecting pitch and direction (pitch and
direction information is relayed to the cortex by separate pathways).

Auditory association cortex surrounds the primary auditory cortex from which it receives
input. The association cortex is required to extract meanings of sound patterns and associate learned
significance with a particular sound pattern.

auditory
association
cortex

primary
auditory cortex

95
 Lecture 16

Visual System
EYEBALL — composed of three concentric layers:
1] SCLERA (white) and CORNEA (transparent) = outer, fibrous layer.
2] IRIS, CILIARY BODY and CHOROID = middle, vascular layer (uvea).
The choroid contains a tapetum lucidum in most domestic animals (absent in the pig).
3] RETINA = inner layer of the eyeball (develops embryologically from an optic cup).
The pigmented epithelium of the retina lines the iris, ciliary body & choroid.
The functional optic part of retina lines the fundus to the level of the ora serrata.

Fundus of Right Eye

Tapetum
Ciliary body lucidum
Iris Retina RETINA
area vessel
Cornea Lens
centralis

Optic disc Area

ora serrata centralis Optic disc

Sclera (visual
streak)

Optic nerve

RETINA
Overview. The retina develops from the optic cup of the diencephalon, and the optic nerve is
histologically a CNS tract. Ten histological layers are recognized in the optic part of the retina. Light
must penetrate eight of the layers to reach outer segments of rods and cones where photons are
absorbed. Processes of pigmented epithelial cells surround the outer segments of rods and cones.
Pigmented epithelial cells are a source of Vitamin A that rods and cones convert to retinal, the photon absorbing
molecule.

Circuitry. Photoreceptor cells (rods and

cones) synapse on bipolar cells which, in turn,
synapse on ganglion cells. Photoreceptor cells
also synapse on horizontal cells which provide
lateral inhibition to sharpen the visual image, as
do amacrine cells.

Nonmyelinated axons of ganglion cells run to

the optic disk and then exit the eyeball as myeli-
nated axons that comprise the optic nerve. Photo-
receptor cells are absent at the optic disc (blind
spot). Retinal vessels enter at the disc and course
along the retinal surface.

96
Photoreceptor cells:
There are two populations
of photoreceptor cells: rods & Sclera
Retinal
cones. The outer segments of Layers: Choroid
rods & cones contain stacked
1. pigmented Retina
membranous discs that are epithelium
continually produced,
sloughed, and phagocytized by 2. rods & cones
pigmented epithelium. The 3. ext. limiting membrane
discs contain the photosensi- 4. outer nuclear
tive pigment (retinal) that 5. outer plexiform
intercepts photons. radial
bipolar horizontal c.
Photoreceptor cells are amacrine c.
glial
cells cell
excited (depolarized) in the 6. inner nuclear
dark and inhibited (repolar-
ized) by light (photons). (astro
7. inner plexiform cyte)
Excitation (depolarization)
spreads electrotonically and
8. ganglion cell
triggers proportional release of
glutamate neurotransmitter 9. optic n. fiber
10. int. limiting membrane
which either excites or inhibits area centralis
the bipolar cells they synapse on.

Bipolar cells:
In general, bipolar cells are spontaneously active, and they are either hyperpolarized (inhibited)
or depolarized (excited) by photoreceptor cells. Bipolar cells generate electrotonic potentials and
they synapse on ganglion cells (as well as some amacrine cells).
Bipolar cells associated with rods form convergent circuits (spatial summation), which improves
vision in dim light but at the expense of image resolution. Bipolar cells associated with cones form
relay circuits (temporal summation) which provides good visual detail but requires bright light.

RODS CONES
• 95% of photoreceptor cells disks • 5% of photoreceptor cells (in
(in human retina) human retina)
• widely disributed Outer • concentrated in the Area
throughtout the retina segment Centralis of the retina
• single population all contain- • multiple populations, based
outer limiting
ing rhodopsin (protein + membrane
on different wavelength
retinal) and the same wave- (color) sensitivities due to
length (color) sensitivity Inner protein differences (protein +
mitochondria

segment retinal)
• functional in dim light
• participate in highly conver- • operate under bright light
nucleus
gent circuits (>1,000 rods conditions
converge on one ganglion • participate in relay circuits
cell) (few cones per ganglion cell)
• exhibit spatial summation • exhibit temporal summation
Rod Cone

97
 Transduction: Photon to Neural Signal

Transduction = converion of energy from one type to another = converting photon energy into neural signals.

Dark condition in rods . . .

• Rhodopsin builds up in the rod outer segment.
Rhodopsin = protein (scotopsin) bound to retinal (11-cis Vitamin A aldehyde)
• cGMP is abundant and acts to keep cation channels open.
• Na+ and Ca++ influx depolarizes the rod cell in a graded electrotonic manner (-40 mV).
• The depolarized rod cell releases glutamate at its synapse with bipolar and horizontal cells.

Photon effect in rods . . .

• Photon energy converts cis-retinal to all trans-retinal, destabilizing rhodopsin which becomes enzymatically
active as it dissociates.
• Activated rhodopsin triggers a G protein (transducin) to activated many phosphodiesterase molecules which
enzymatically convert cGMP to GMP.
• Cation channels close in the absence of cGMP and the rod cell becomes polarized (-70 mV).
(One photon activates one rhodopsin molecule which triggers closure of hundreds of cation channels.)
• The rod cell releases less glutamate at its synapse.
Note: Transduction is the same in cones, except that the protein is different (not scotopsin).

Ganglion cells
Ganglion cell axons leave the retina and form the optic nerve. Unlike all other retinal cells,
ganglion cells generate action potentials. They fire continuosly, and the presence/absence of light
merely changes their firing rates.
Ganglion cells respond to a spot of light with a center "ON/surround-OFF" pattern
(or an "OFF/ON" pattern), i.e., the spot causes stimulated ganglion cells to increase
their firing rates and lateral inhibition (by horizontal cells) causes surrounding ganglion
cells to decrease their firing rates.

Three functionally different populations of ganglion cells have been discovered:

1] Large cells that receive rod input from a broad area and signal motion, position, and depth;
2] Small cells with small receptive fields that are unaffected by color differences; and
3] Small cells that are color sensitive, i.e., excited by one color and inhibited by another.

Other retinal cells

Horizontal cells are always inhibitory. They are primarily responsible for lateral inhibition, i.e.,
the inhibition that surrounds the excitation generated by a spot of light.

Amacrine cells are often inhibitory neurons that make synaptic contact with bipolar & ganglion
cells. Some respond to the onset/offset of light, others are responsive to direction of light movement.
The optic nerve contains efferent axons which synapse on amacrine cells to provide brain control of
retinal activity. There are 30 different populations of amacrine cells with respect to morphology and neurotransmitters
released.

Radial glial cells (Mueller cells): modified astrocytes which provide structural and metabolic
support. Like astrocytes they take up excess ions and neurotransmitter molecules to maintain homeo-
stasis. Processes of these cells form the internal and external limiting membranes.
98
 VISUAL PATHWAY
Optic nerve — axons from ganglion cells of the retina (1.5 million axons in human; 0.2 million in dog)

Optic chiasm (chiasma) — optic nerve axons decussate, except that a percentage of axons from
the lateral side of each retina do not cross, depending on species:
— in submammalian vertebrates, e.g., fish, 100% of optic fibers cross in the chiasm
— in domestic animals: horse 90%; sheep 88%; pig 72%; dog 75%; cat 63% cross
— in human: 50% of optic nerve fibers cross in the optic chiasma.
(NOTE: % crossing is related to eye position in the head and visual field overlap)

Optic tract —axons from both eyes. The optic tract conveys contralateral visual field
information (i.e., axons from the lateral part of the retina of the ipsilateral eye &
the medial & central parts of the retina of the contralateral eye).

Visual Fields

Binocular vision,
which is important for OVERLAP
depth perception,
requires visual field
overlap so that
Left field Right field
individual objects can
be viewed simulta-
neously by both eyes.

For binocular
vision to occur, the
visual cortex in one
cerebral hemisphere
must receive informa-
tion about an object
from both eyes.

This requires that

“corresponding”
ganglion cells in each Optic nerve
eye send their axons
through the same optic
Optic chiasma
tract. In visual cortex,
some columns monitor
stimulation in corre- Visual Optic tract
sponding loci of the cortex
two eyes.
Lateral
geniculate Brachium
The cerebral optic radiation of the
cortex controls (internal rostral
extraocular eye capsule) colliculus
muscles so that Pretectal
corresponding points region
in each retina view the
same object (otherwise Rostral
double vision ensues). colliculus

99
 Conscious Visual Pathway
Optic tract fibers synapse in the lateral geniculate nucleus, which exhibits a retinotopic organi-
zation and "ON/surround-OFF" receptor fields. Neurons of the lateral geniculate nucleus send their
axons into the optic radiation of the internal capsule and then to the visual cortex. Actually, the lateral
geniculate nucleus is stratified, with input from each eye and large/small ganglion cell input entering different layers.

The visual cortex is retinotopically organized. Representation of the area centralis is greatly
enlarged compared to cortical surface area devoted to the rest of the retina.
The visual cortex exhibits the typical columnar organization of neocortex. Columns respond to
the geometric & dynamic elements of an image. A cell column within visual cortex becomes excited
in response to light–dark boundaries oriented at a certain angle, moving in a certain direction, affect-
ing either or both eyes, etc. Some cell columns are activated by particular colors.

Association cortex, surrounding the primary visual cortex, is required to associate meaning and
significance to the elements of the primary image. There are two separate visual integrations:
1] A phylogenetically older "where" system that analyzes motion and depth. Damage produces:
— failed ocular pursuit of a moving target, i.e., inaccurate eye saccades (tiny movements);
— poor depth perception (astereopsis);
— deficient visually guided movements, e.g., reaching (optic ataxia); and
— deficits in visual attention.
2] A phylogenetically newer "what" system that analyzes form and color. Damage produces:
— loss of color vision;
— impaired pattern recognition, including face/object recognition (visual agnosia).

Three principles of conscious visual transmission are:

• Retinotopic mapping — eventually lost at level of association cortex
• Parallel processing — color/form/motion remain separate from retina to cortex
• Hierarchial processing — receptive fields become larger and more complex at each level.

Color Vision
Humans have three populations of color senstive cones. We are trichomatic
and can distinguish the range of colors with which you are familiar.
Color vision in dogs is said to be comparable to people who are red-green
color blind. Dogs are dichromatic and seem to see blue and yellow but not green or
orange-red.
All of several horses tested could distinguish red and blue from gray. Some
but not all of the horses could also distinguish yellow and green from gray.
Two populations of color senstive cones are found in other species, e.g., cat
and pig. Nocturnal animals are completely color blind (rat, hampster, etc.).

Reflex Visual Pathways

Axons participating in subconscious visual reflexes leave the optic tract and travel in the bra-
chium of the rostral colliculus to reach two visual reflex centers, the rostral colliculus and the
pretectal region. (Axons also leave the optic tract to reach the hypothalamus.)

100
 Two important visual reflexes are:
1] Eye, ear and head turning to orient to a sudden, prominent visual stimulus involves the
rostral colliculus. Neurons of the rostral colliculus send their axons to appropriate motor nuclei via
tectobulbar and tectospinal tracts. (The rostral colliculus is used by visual cortex for subconsious eye
movements.)
In higher mammals, the rostral colliculus depends on input from the cerebral cortex to function and
cortical damage produces apparent total blindness. In birds, the rostral colliculus equivalent (optic lobe)
provides all visual function.

2] Pupil size regulation to compensate for light intensity involves the pretectal region, with
fiber decussation in the caudal commissure. Axons go to the parasympathetic nucleus of the
oculomotor nerve for pupillary constriction (dilation is achieved by less constriction).
Pupil dilation in response to emotional situations (fight/flight) involves sympathetic preganglionic
neurons in the cranial thoracic spinal cord. Pupil constriction in response to accommodation for near vision is
controlled by the cerebral cortex.

Pupil Size — Reflex Pathways

Pupil (light sensitive)
Retina
constriction
ciliary nerve
Optic nerve
Optic chiasma ciliary ganglion
Optic tract Lateral oculomotor nerve
geniculate
Brachium
of rhe
rostral Pupil (emotion-related)
colliculus dilation
Pretectal region plexus on
and internal
Caudal commissure carotid A.

cranial
Oculomotor cervical
nucleus ganglion

cervical
sympathetic
trunk
Cervical spinal cord

Spinal cord
segment T-1

101